Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid

ABSTRACT

The present invention relates to pyrrolidin-2-ones according to the formula (1), or salts thereof, 
                         
wherein R1 is hydrogen or a nitrogen protecting group, methods for their preparation and their use in the preparation of NEP-inhibitors, particularly in the preparation of N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester or salt thereof.

This application is a Divisional application of Ser. No. 13/333,437,filed Dec. 21, 2011, which is a Divisional application of Ser. No.12/522,767, filed Jul. 10, 2009, which is a National Phase Applicationof PCT/EP2008/000142, filed Jan. 10, 2008, which claims benefit of EP07/100,451.9, filed Jan. 10, 2008.

The present invention relates to pyrrolidin-2-ones according to formula(1), or salts thereof,

wherein R1 is hydrogen or a nitrogen protecting group, as definedherein, methods for their preparation and their use in the preparationof NEP-inhibitors, particularly in the preparation ofN-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester, or salt thereof.

Endogenous atrial natriuretic peptides (ANP), also called atrialnatriuretic factors (ANF), have diuretic, natriuretic and vasorelaxantfunctions in mammals. The natural ANF peptides are metabolicallyinactivated, in particular by a degrading enzyme which has beenrecognized to correspond to the enzyme neutral endopeptidase (NEP, EC3.4.24.11), which is also responsible for e.g. the metabolicinactivation of enkephalins.

In the art biaryl substituted phosphonic acid derivatives are knownwhich are useful as neutral endopeptidase (NEP) inhibitors, e.g. asinhibitors of the ANF-degrading enzyme in mammals so as to prolong andpotentiate the diuretic, natriuretic and vasodilator properties of ANFin mammals by inhibiting the degradation thereof to less activemetabolites. NEP inhibitors are thus particularly useful for thetreatment of conditions and disorders responsive to the inhibition ofneutral endopeptidase (EC 3.4.24.11), particularly cardiovasculardisorders such as hypertension, renal insufficiency including edema andsalt retention, pulmonary edema and congestive heart failure.

Processes for preparing NEP-inhibitors are known.

U.S. Pat. No. 5,217,996 describes biaryl substituted 4-amino-butyricacid amide derivatives which are useful as neutral endopeptidase (NEP)inhibitors, e.g. as inhibitors of the ANF-degrading enzyme in mammals.As a preferred embodiment U.S. Pat. No. 5,217,996 disclosesN-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester and a method for its preparation.

Several dicarboxylic acid dipeptide neutral endopeptidase (NEP)inhibitors are further described in G. M. Ksander et al., J. Med. Chem.1995, 38, 1689-1700, “Dicarboxylic Acid Dipeptide Neutral EndopeptidaseInhibitors”. Among others,N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester and a method for its preparation aredisclosed.

It was an object of the present invention to provide an alternativereaction route in a process for producing NEP inhibitors or prodrugsthereof, in particular it was an object to provide an alternativereaction route in a process for producingN-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester, or salt thereof.

U.S. Pat. No. 5,217,996 discloses the preparation ofN-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester. In the preparation of said compoundN-t-butoxycarbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoicacid ethyl ester is hydrogenated in the presence of palladium oncharcoal. A major drawback of said process is that such a hydrogenationstep is not very selective and yieldsN-t-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoicacid ethyl ester as a 80:20 mixture of diastereomers. Moreover, theprocess for preparingN-t-butoxycarbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-(2)-methyl(2)-butenoicacid ethyl ester requires D-tyrosine as starting material, which is anunnatural amino acid and is not readily available.

It was hence an object of the present invention to provide analternative reaction route

for preparing compoundN-t-butoxycarbonyl(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoicacid ethyl ester, or salt thereof, preferably a reaction route whichavoids the above-mentioned drawbacks of the prior art process. Inparticular, it was an object of the present invention to provide aprocess for preparing compoundN-t-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester, or salt thereof, wherein the above-mentionedhydrogenation step is avoided.

It was a still further object to provide a process for producingcompoundN-t-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoicacid ethyl ester, or salt thereof, having a high diastereomeric ratio,wherein the (2R,4S)-configuration according to formula (3-a) ispreferred. In particular, the diastereomeric ratio is desirably morethan 60:40, preferably more than 70:30, particularly preferred more than80:20. More preferred the diastereomeric ratio is more than 90:10. Thediastereomeric ratio can be up to 99:1, preferably 100:0. Preferreddiasteromeric ratios refer to the ratio of diasteromers (3-a) to (3-b),or salts thereof,

wherein R1 is H, R2 is t-butoxycarbonyl and R3 is ethyl. The conversionof a compound of formula (3),

wherein R1 is H, R2 is t-butoxycarbonyl and R3 is ethyl, into a NEPinhibitor or prodrug thereof, in particular intoN-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester, or salt thereof, has been described, forexample in the Journal of Medicinal Chemistry, 1995, 38, 1689.

It was also an object to provide an alternative process, wherein theresulting compoundN-t-butoxycarbonyl(4S)-(p-phenylphenylmethyl)-4-amino-(2R)methyl-butanoicacid ethyl ester, or salt thereof, can be provided in pure or even incrystalline form.

Furthermore, it was an object of the present invention to provide aprocess wherein readily available starting compounds, e.g. natural aminoacids or derivatives thereof, can be used and unnatural amino acids asstarting material are avoided. Preferably it was an object of thepresent invention to provide a process wherein the starting materialsare available from the chiral pool.

The objects of the present invention can be achieved by providing aspecific lactam as a key intermediate. Starting from that specificlactam, advantageous reaction routes producing the desiredNEP-inhibitors and prodrugs thereof are possible.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows a X-ray structure of(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one.

FIG. 2 shows a X-ray structure of(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one.

FIG. 3 shows a X-ray structure of(3S,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one.

FIG. 4 shows a X-ray structure of(S)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one.

FIG. 5 shows a X-ray structure of(2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid hydrochloride.

FIG. 6 a shows a X-ray structure of(2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl esterhydrochloride.

FIG. 6 b shows a X-ray structure of(2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl esterhydrochloride.

FIG. 7 shows a X-ray structure of(3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one.

FIG. 8 shows a X-ray structure of(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester.

FIG. 9 shows a X-ray structure of(S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one.

FIG. 10 shows a X-ray structure of(S)-5-biphenyl-4-ylmethyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butylester.

FIG. 11 shows a X-ray structure of (S)-4-Amino-5-biphenyl-4-yl-pentanoicacid ethyl ester hydrochloride.

Therefore, the subject-matter of the present invention is apyrrolidin-2-one according to formula (1), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, as definedhereinafter.

The compound according to formula (1), or salt thereof, is hereinafterreferred to as “Key Lactam (1)”.

The invention as a whole comprises the following sections:

-   Section A: The Key Lactam (1) as such-   Section B: Use of the Key Lactam (1) in the preparation of    NEP-inhibitors-   Section C: Preparation methods for the Key Lactam (1)-   Section D: Novel and inventive compounds occurring in one of the    precedent sections-   Section E: Examples

The invention specially relates to the processes described in eachsection. The invention likewise relates, independently, to every singlestep described in a process sequence within the corresponding section.Therefore, each and every single step of any process, consisting of asequence of steps, described herein is itself a preferred embodiment ofthe present invention. Thus, the invention also relates to thoseembodiments of the process, according to which a compound obtainable asan intermediate in any step of the process is used as a startingmaterial.

The invention likewise relates to novel starting materials which havebeen specifically developed for the preparation of the compoundsaccording to the invention, to their use and to processes for theirpreparation.

It is noted that in the present application usually explanations made inone section are also applicable for other sections, unless otherwisestated. For example, the explanations for the residue R1 in formula (1)given in section A also apply if formula (1) occurs in sections B, C, Dand E, unless otherwise stated. When referring to compounds described inthe present invention, it is understood that reference is also beingmade to salts thereof. Depending on the choice of the starting materialsand procedures, the compounds can be present in the form of one of thepossible isomers or as mixtures thereof, for example as pure opticalisomers, or as isomer mixtures, such as racemates and diastereoisomermixtures, depending on the number of asymmetric carbon atoms.

Section A: The Key Lactam (1) As Such

The subject-matter of the present invention is a lactam according toformula (1), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, as definedhereinafter.

With regard to formula (1), two enantiomers according to formulae (1-a)and (1-b), or salts thereof, are possible.

In the present invention compounds according to formula (1-a)(═S-enantiomer) are preferred. In formulae (1), (1-a) and (1-b), orsalts thereof, the residue R1 is hydrogen or a nitrogen protectinggroup, as defined hereinafter, preferably the nitrogen protecting groupis pivaloyl, pyrrolidinylmethyl, t-butoxycarbonyl, benzyl, silyl (suchas TES), acetyl, benzyloxycarbonyl (Cbz) and trimethylsilyethoxymethyl(SEM); more preferably pivaloyl, pyrrolidinylmethyl, t-butoxycarbonyl,benzyl and silyl (such as TES).

Generally, in the present application all pyrrolidin-2-one compounds, orsalts thereof, are usually shown in their keto form. However, in view ofthe possibly occurring keto-enol-tautomerism the present inventionconcerns also the described compounds, or salts thereof, in theircorresponding enol form, as shown below, wherein the asterisk (*)denotes the point of binding to the rest of the molecule.

In case of formula (1) a corresponding enol derivative is shown informula (1′):

wherein R1 is hydrogen or a nitrogen protecting group, as definedhereinafter, and R1′ is hydrogen or an oxygen protecting group, asdefined hereinafter.

The above applies to all respective compounds of the present inventionhaving a pyrrolidin-2-one structure, in particular for compoundsaccording to formulae (1), (2), (4), (5), (12) and (13), or saltsthereof, as well as for compounds having a preferred configuration asshown in formulae (1-a), (2-a), (4-a), (5-a), (12-a) and (13-a), orsalts thereof.

In the present application the term “nitrogen protecting group”generally comprises any group which is capable of reversibly protectinga nitrogen functionality, preferably an amino and/or amidefunctionality. The term “oxygen protecting group” generally comprisesany group which is capable of reversibly protecting the oxygenfunctionality.

Preferably the nitrogen protecting group is an amine protecting groupand/or an amide protecting group. Suitable nitrogen protecting groupsare conventionally used in peptide chemistry and are described e.g. inthe relevant chapters of standard reference works such as J. F. W.McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, Londonand New York 1973, in T. W. Greene and P. G. M. Wuts, “Protective Groupsin Organic Synthesis”, Third edition, Wiley, New York 1999, in “ThePeptides”; Volume 3 (editors: E. Gross and J. Meienhofer), AcademicPress, London and New York 1981, and in “Methoden der organischenChemie” (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume15/I, Georg Thieme Verlag, Stuttgart 1974.

Preferred nitrogen protecting groups generally comprise:

C₁-C₆-alkyl, preferably C₁-C₄-alkyl, more preferably C₁-C₂-alkyl, mostpreferably C₁-alkyl which is mono-, di- or tri-substituted bytrialkylsilylC₁-C₇-alkoxy (eg. trimethylsilyethoxy)aryl, preferablyphenyl, or an heterocyclic group, preferably pyrrolidinyl, wherein thearyl ring or the heterocyclic group is unsubstituted or substituted byone or more, e.g. two or three, residues, e.g. selected from the groupconsisting of C₁-C₇-alkyl, hydroxy, C₁-C₇-alkoxy, C₂-C₈-alkanoyl-oxy,halogen, nitro, cyano, and CF₃;aryl-C1-C2-alkoxycarbonyl (preferably phenyl-C1-C2-alkoxycarbonyl eg.benzyloxycarbonyl); C₁₋₁₀alkenyloxycarbonyl; C₁₋₆alkylcarbonyl (eg.acetyl or pivaloyl); C₆₋₁₀arylcarbonyl; C₁₋₆alkoxycarbonyl (eg.t-butoxycarbonyl); C₆₋₁₀arylC₁₋₆alkoxycarbonyl; allyl or cinnamyl;sulfonyl or sulfenyl; succinimidyl group, silyl, e.g. triarylsilyl ortrialkylsilyl (eg. triethylsilyl).

Examples of preferred nitrogen protecting groups are acetyl, benzyl,cumyl, benzhydryl, trityl, benzyloxycarbonyl (Cbz),9-fluorenylmethyloxycarbony (Fmoc), benzyloxymethyl (BOM),pivaloyl-oxy-methyl (POM), trichloroethxoycarbonyl (Troc),1-adamantyloxycarbonyl (Adoc), allyl, allyloxycarbonyl, trimethylsilyl,tert.-butyl-dimethylsilyl, triethylsilyl (TES), triisopropylsilyl,trimethylsilyethoxymethyl (SEM), t-butoxycarbonyl (BOC), t-butyl,1-methyl-1,1-dimethylbenzyl, (phenyl)methyl benzene, pyrridinyl andpivaloyl. Most preferred nitrogen protecting groups are acetyl, benzyl,benzyloxycarbonyl (Cbz), triethylsilyl (TES), trimethylsilyethoxymethyl(SEM), t-butoxycarbonyl (BOC), pyrrolidinylmethyl and pivaloyl.

Examples of more preferred nitrogen protecting groups are pivaloyl,pyrrolidinylmethyl, t-butoxycarbonyl, benzyl and silyl groups,particularly silyl groups according to the formula SiR7R8R9, wherein R7,R8 and R9 are, independently of each other, alkyl or aryl. Preferredexamples for R7, R8 and R9 are methyl, ethyl, isopropyl, t-butyl andphenyl.

Particularly preferred as nitrogen protecting groups are pivaloyl andt-butoxycarbonyl (BOC).

Preferred oxygen protecting groups are silyl groups according to theformula SiR7R8R9, wherein R7, R8 and R9 are, independently of eachother, alkyl or aryl. Preferred examples for R7, R8 and R9 are methyl,ethyl, isopropyl, t-butyl and phenyl. In particular, R7, R8 and R9 areethyl or methyl. Particular preferred oxygen protecting groups are SiMe₃and SiEt₃.

Alkyl being a radical or part of a radical is a straight or branch (oneor, if desired and possible, more times) carbon chain, and is especiallyC₁-C₇-alkyl, preferably C₁-C₄-alkyl.

The term “C₁-C₇-” defines a moiety with up to and including maximally 7,especially up to and including maximally 4, carbon atoms, said moietybeing branched (one or more times) or straight-chained and bound via aterminal or a non-terminal carbon

Cycloalkyl is, for example, C₃-C₇-cycloalkyl and is, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.Cyclopentyl and cyclohexyl are preferred.

Alkoxy is, for example, C₁-C₇-alkoxy and is, for example, methoxy,ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy,sec-butyloxy, tert-butyloxy and also includes corresponding pentyloxy,hexyloxy and heptyloxy radicals. C₁-C₄alkoxy is preferred.

Alkanoyl is, for example, C₂-C₈-alkanoyl and is, for example, acetyl[—C(═O)Me], propionyl, butyryl, isobutyryl or pivaloyl. C₂-C₅-Alkanoylis preferred, especially acetyl.

Halo or halogen is preferably fluoro, chloro, bromo or iodo, mostpreferably fluoro, chloro or bromo.

Halo-alkyl is, for example, halo-C₁-C₇alkyl and is in particularhalo-C₁-C₄alkyl, such as trifluoromethyl, 1,1,2-trifluoro-2-chloroethylor chloromethyl. Preferred halo-C₁-C₇alkyl is trifluoromethyl.

Alkenyl may be linear or branched alkyl containing a double bond andcomprising preferably 2 to 12 C atoms, 2 to 10 C atoms being especiallypreferred. Particularly preferred is a linear C₂₋₄alkenyl. Some examplesof alkyl groups are ethyl and the isomers of propyl, butyl, pentyl,hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl,hexadecyl, octacyl and eicosyl, each of which containing a double bond.Especially preferred is allyl.

Alkylene is a bivalent radical derived from C₁₋₇alkyl and is especiallyC₂-C₇-alkylene or C₂-C₇-alkylene which is interrupted by, one or more,O, NR14 or S, wherein R14 is alkyl, each of which can be unsubstitutedor substituted, by one or more substituents independently selected fromfor example, C₁-C₇-alkyl, C₁-C₇-alkoxy-C₁-C₇-alkyl or C₁-C₇-alkoxy.

Alkenylene is a bivalent radical derived from C₂₋₇alkenyl and can beinterrupted by, one or more, O, NR14 or S, wherein R14 is alkyl, and isunsubstituted or substituted by one or more, e.g. up to three,substitutents preferably independently selected from the substitutentsmentioned above for alkylene.

Aryl being a radical or part of a radical is, for example C₆₋₁₀aryl, andis, preferably a mono- or polycyclic, especially monocyclic, bicyclic ortricyclic aryl moiety with 6 to 10 carbon atoms, preferably phenyl, andwhich can be unsubstituted or substituted, by one or more substituentsindependently selected from for example, C₁-C₇-alkoxy-C₁-C₇-alkyl orC₁-C₇-alkoxy.

Aryloxy refers to a Aryl-O— wherein aryl is as defined above.

Unsubstituted or substituted heterocyclyl is a mono- or polycyclic,preferably a mono-, bi- or tricyclic-, most preferably mono-,unsaturated, partially saturated, saturated or aromatic ring system withpreferably 3 to 14 (more preferably 5 to 14) ring atoms and with one ormore, preferably one to four, heteroatoms independently selected fromnitrogen, oxygen, sulfur, S(═O)— or S-(═O)₂, and is unsubstituted orsubstituted by one or more, e.g. up to three, substitutents preferablyindependently selected from the Preferred substituents are selected fromthe group consisting of halo, C₁-C₇-alkyl, C₁-C₇-alkoxy,halo-C₁-C₇-alkoxy, such as trifluoromethoxy andC₁-C₇-alkoxy-C₁-C₇-alkoxy. When the heterocyclyl is an aromatic ringsystem, it is also referred to as heteroaryl.

Acetyl is —C(═O)C₁-C₇alkyl, preferably —C(═O)Me.

Silyl is —SiRR′R″, wherein R, R′ and R″ are independently of each otherC₁₋₇alkyl, aryl or phenyl-C₁₋₄alkyl.

Sulfonyl is (unsubstituted or substituted) C₁-C₇-alkylsulfonyl, such asmethylsulfonyl, (unsubstituted or substituted) phenyl- ornaphthyl-C₁-C₇-alkyl-sulfonyl, such as phenylmethanesulfonyl, or(unsubstituted or substituted) phenyl- or naphthyl-sulfonyl; wherein ifmore than one substituent is present, e.g. one to three substitutents,the substituents are selected independently from cyano, halo,halo-C₁-C₇alkyl, halo-C₁-C₇-alkyloxy- and C₁-C₇-alkyloxy. Especiallypreferred is C₁-C₇-alkylsulfonyl, such as methylsulfonyl, and (phenyl-or naphthyl)-C₁-C₇-alkyl-sulfonyl, such as phenylmethanesulfonyl.

Sulfenyl is (unsubstituted or substituted) C₆₋₁₀aryl-C₁-C₇-alkylsulfenylor (unsubstituted or substituted) C₆₋₁₀arylsulfenyl, wherein if morethan one substituent is present, e.g. one to four substitutents, thesubstituents are selected independently from nitro, halo,halo-C₁-C₇alkyl and C₁-C₇-alkyloxy.

The term “saponification reagent” is to be understood as a base which isable to hydrolyze an ester to form an alcohol and the salt of acarboxylic acid, eg. an alkali metal hydroxide such as KOH or NaOH.

The term “group which can be saponified” is to be understood as an estergroup —CO₂R wherein R is alkyl, aryl or arylalkyl, which can behydrolized, for example under basic conditions (e.g. alkalimetal basesuch as. NaOH, LiOH or KOH) or under acidic conditions (eg. by the useof mineral acids, such as HCl, H₂SO₄, HBr, H₃PO₄) to provide acarboxylic acid. As an extension, the term “group which can besaponified” can also include an ester group —CO₂R wherein R is aryl orarylalkyl, which can be reacted by use of a hydrogenation catalyst (egPd/C, Pt/C, Rh/C, Pd/Al₂O₃, PtO₂), in the presence of an acid (eg.acetic acid) or a base (eg. triethylamine) or under neutral conditions,to provide a carboxylic acid.

The term “group which can be decarboxylated” is to be understood as agroup —CO₂R, wherein R is hydrogen, alkyl, aryl or arylalkyl, which canbe replaced by hydrogen under reaction conditions such as heating,optionally in the presence of a solvent, preferably initiated byboiling. An extension of this definition can include an ester group—CO₂M, wherein M is an alkali metal, for example Na or K, in thepresence of a crown ether, for example, 18-crown-6. Suitable solventsare, for example, toluene, o-/m-/p-xylene, benzene, THF, 1,4-dioxane,DMF, water, tert-butyl methyl ether. Preferably a high boiling solventis used, ideally a solvent with a boiling point at atmospheric pressureof more than 50° C. More preferably, a solvent with a boiling point ofmore than 100° C.

The term “tautomer” refers in particular to the enol tautomer of thepyrrolidin-2-one moiety of the compounds of the present invention.

The term “biphenyl” or “biphenylic” in expressions herein, such as,“biphenyl magnesium halide” or “biphenylic compound”, are to beunderstood as meaning 4-biphenyl or 4-biphenylic, also calledpara-biphenyl or para-biphenylic, for example 4-biphenylmagnesiumbromide or 4-bromobiphenyl.

The terms “PG”, “PG1” and “PG2” refer, independently, to a nitrogenprotecting group as defined herein.

In the formulae of the present application the term “

” on a C-sp³ represents a covalent bond, wherein the stereochemistry ofthe bond is not defined. This means that the term “

” on a C-sp³ comprises an (S) configuration as well as an (R)configuration of the respective chiral centre. Furthermore, mixtures arealso encompassed.

In the formulae of the present application the term “

” on a C-sp³ indicates the absolute stereochemistry, either (R) or (S).

In the formulae of the present application the term “

” on a C-sp³ indicates the absolute stereochemistry, either (R) or (S).

Salts are especially pharmaceutically acceptable salts or generallysalts of any of the intermediates mentioned herein, where salts are notexcluded for chemical reasons the skilled person will readilyunderstand. They can be formed where salt forming groups, such as basicor acidic groups, are present that can exist in dissociated form atleast partially, e.g. in a pH range from 4 to 10 in aqueous solutions,or can be isolated especially in solid, especially crystalline, form.

Such salts are formed, for example, as acid addition salts, preferablywith organic or inorganic acids, from compounds or any of theintermediates mentioned herein with a basic nitrogen atom (e.g. imino oramino), especially the pharmaceutically acceptable salts. Suitableinorganic acids are, for example, halogen acids, such as hydrochloricacid, sulfuric acid, or phosphoric acid. Suitable organic acids are, forexample, carboxylic, phosphonic, sulfonic or sulfamic acids, for exampleacetic acid, propionic acid, lactic acid, fumaric acid, succinic acid,citric acid, amino acids, such as glutamic acid or aspartic acid, maleicacid, hydroxymaleic acid, methylmaleic acid, benzoic acid, methane- orethane-sulfonic acid, ethane-1,2-di-sulfonic acid, benzenesulfonic acid,2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid,N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamicacid, or other organic protonic acids, such as ascorbic acid.

In the presence of negatively charged radicals, such as carboxy orsulfo, salts may also be formed with bases, e.g. metal or ammoniumsalts, such as alkali metal or alkaline earth metal salts, for examplesodium, potassium, magnesium or calcium salts, or ammonium salts withammonia or suitable organic amines, such as tertiary monoamines, forexample triethylamine or tri(2-hydroxyethyl)amine, or heterocyclicbases, for example N-ethyl-piperidine or N,N′-dimethylpiperazine.

When a basic group and an acid group are present in the same molecule,any of the intermediates mentioned herein may also form internal salts.

For isolation or purification purposes of any of the intermediatesmentioned herein it is also possible to use pharmaceuticallyunacceptable salts, for example picrates or perchlorates.

In view of the close relationship between the compounds andintermediates in free form and in the form of their salts, includingthose salts that can be used as intermediates, for example in thepurification or identification of the compounds or salts thereof, anyreference to “compounds”, “starting materials” and “intermediates”hereinbefore and hereinafter is to be understood as referring also toone or more salts thereof or a mixture of a corresponding free compound,intermediate or starting material and one or more salts thereof, each ofwhich is intended to include also any solvate or salt of any one or moreof these, as appropriate and expedient and if not explicitly mentionedotherwise. Different crystal forms may be obtainable and then are alsoincluded.

Where the plural form is used for compounds, starting materials,intermediates, salts, pharmaceutical preparations, diseases, disordersand the like, this is intended to mean one (preferred) or more singlecompound(s), salt(s), pharmaceutical preparation(s), disease(s),disorder(s) or the like, where the singular or the indefinite article(“a”, “an”) is used, this is not intended to exclude the plural, butonly preferably means “one”.

The compounds of the present invention can possess one or moreasymmetric centers. The preferred absolute configurations are asindicated herein specifically. However, any possible pure enantiomer,pure diastereoisomer, or mixtures thereof, e.g., mixtures ofenantiomers, such as racemates, are encompassed by the presentinvention.

The Key Lactam according to formula (1), or salt thereof, wherein R1 ishydrogen can be converted into a Key Lactam according to formula (1), orsalt thereof, wherein R1 is a nitrogen protecting group, as definedabove, according to standard methods of organic chemistry known in theart, in particular reference is made to conventional nitrogen protectinggroup methods described in J. F. W. McOmie, “Protective Groups inOrganic Chemistry”, Plenum Press, London and New York 1973, in T. W.Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”,Third edition, Wiley, New York 1999 and in Richard C. Larock,“Comprehensive Organic Transformations: A Guide to Functional GroupPreparations”, Second Edition, Wiley-VCH Verlag GmbH, 2000.

The same applies for the Key Lactam according to formula (1′), or saltthereof, wherein R1′ is hydrogen. The conversion of R1′ from hydrogen toan oxygen protecting group, as defined above, can be carried out byknown methods; standard conditions for such methods are described, forexample in reference books above-mentioned.

In a first preferred embodiment, R1′ is hydrogen and R1 is a silylprotecting group, as defined below. In a second preferred embodiment, R1and R1′ are both a silyl protecting group, as defined below. Thepreparation of compounds of according to these two embodiments can beaccomplished, for example, as described in U.S. Pat. No. 4,604,383.According to the second preferred embodiment, compounds according toformula (1″), or salts thereof, are provided

wherein R7, R8 and R9 are independently, of each other, aryl or alkyl,preferably methyl or ethyl. Preferred examples for R7, R8 and R9 aremethyl, ethyl, isopropyl, t-butyl, phenyl. In particular, R7, R8 and R9are ethyl or methyl. Particular preferred protecting groups are SiMe₃and SiEt₃.

As mentioned above, the preferred stereochemical configuration isindependent of whether the compounds are provided in the keto form or asenol derivatives.

Thus, in a preferred embodiment compounds according to formula (1″), orsalts thereof, are provided as S-enantiomers according to formula (1″-a)

wherein R7, R8 and R9 are defined as above.

In a preferred embodiment compounds according to formula (1″), or saltsthereof, can be prepared by reacting a compound according to formula(1), or salt thereof, wherein R1 is hydrogen, with a compound R7R8R9SiX,wherein R7, R8 and R9 are defined as above and X is a leaving group,preferably, chlorine, bromine, triflate or tosylate. Preferably, thecompound R7R8R9SiX is trimethylsilyl chloride or triethylsilyl chloride.Preferably, the reaction is carried out in the presence of a base.Preferred bases are triethylamine, diethylamine, lutidine and mixturesthereof. Examples for other suitable bases are LDA and KHMDS.

The formation of the silyl enol derivative according to formula (1″), orsalt thereof, can be carried out under thermodynamic control. Therefore,the reaction can be driven to completion.

Section B: Use Of The Key Lactam In The Preparation Of Nep-Inhibitors

It is a subject of the present invention to use the key lactam accordingto formula (1), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, as defined above,in the synthesis of an NEP-inhibitor or a prodrug thereof. Preferablythe key lactam used has an S-configuration according to formula (1-a).

In a preferred embodiment the NEP-inhibitor prodrug isN-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester, as shown in formula (18), or salt thereof:

Section B of the present invention comprises 3 subsections:

-   Subsection B-1: Reacting a compound (1) to obtain a methylated    lactam (2)-   Subsection B-2: Reacting the methylated lactam (2) to obtain an    intermediate (3)-   Subsection B-3: Reacting the intermediate (3) to obtain a    NEP-inhibitor or prodrug thereof, preferably a NEP-inhibitor prodrug    according to formula (18) or salt thereof.    Subsection B-1: Reacting Compound (1) to Obtain a Methylated Lactam    (2)

Another subject of the present invention is a process for producing acompound according to formula (2) or salt thereof

wherein R1 is hydrogen or a nitrogen protecting group, as defined above,comprising methylating a compound according to formula (1), or saltthereof, preferably methylating a compound of formula (1-a), or saltthereof. Generally, all explanations made above about preferredembodiments of the Key Lactam (1) also apply in the present section.

As stated above, the compound according to formula (2), or salt thereof,is shown in its keto form. However, also the corresponding enol formsaccording to formula (2′) are also comprised by the present invention

wherein R1 is hydrogen or a nitrogen protecting group, as defined above,and R1′ is hydrogen or an oxygen protecting group, as defined above. Ina preferred embodiment, the compound of formula (2′), or salt thereof,is according to formula (2′-a).

Generally, the above-described methylation reaction is carried out inthe presence of a methylating agent. Usually, any methylating agentknown in the art is suitable. Examples for suitable methylating agentsare methyl iodide, methyl bromide, methyl chloride, methyl fluoride,dimethylsulphate, methyl triflate (MeOTf), 4-methylsulfonyltoluene andmixtures thereof. Preferably, methyl iodide or dimethylsulphate ormixtures thereof are used.

The methylation reaction can be performed at a wide temperature range,e.g. between −100° C. and +50° C. Preferably, the reaction is carriedout between −80° C. and +20° C., more preferably the reaction is carriedout between −10° C. and +10° C., most preferably the reaction is carriedout at 0° C. The reaction can be carried out in a variety of solventse.g. tetrahydrofuran (THF), tert-butylmethylether (TBME),1,2-dimethoxyethane, diethyl ether, toluene and mixtures thereof.Preferably, THF or toluene is used.

In a preferred embodiment the reaction is carried out in the presence ofa base. The base is, for example, RcRdNM, wherein Rc and Rd areindependently selected from alkyl, cycloalkyl, heterocyclyl or silyl andM is an alkali metal such as Na, Li or K. Examples for suitable basesare lithium bis(trimethylsilyl)amide (LHMDS), sodiumbis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide(KHMDS), lithium diisopropylamide (LDA), n/sec/tert-butyllithium,isopropylmagnesium chloride, phenyllithium, and mixtures thereof.Alternative suitable bases are lithium dicyclohexylamine and lithiumtetramethylpiperidine. Preferable, LDA, KHMDS or mixtures thereof areused. More preferably the base is lithium tetramethylpiperidine andpotassium bis(trimethylsilyl)amide.

It can also be preferred that a “reaction enhancer” is added. Generally,as reaction enhancer compounds are suitable that improve the solubilityof the formed products or help to deaggregate the base, thereby makingit more reactive. Suitable reaction enhancers are described in relevantchapters in F A Carey, R J Sundberg, Organische Chemie, VCH, Weinheim,1995 (German translation of English original). Examples of preferredreaction enhancers are hexamethylphosphoramide (HMPA),N,N′-dimethylpropyleneurea (DMPU), tetramethylethylenediamine (TMEDA),dimethylsulfoxide (DMSO) or mixtures thereof. Crown ethers or chiralcrown ethers are also suitable for this purpose.

In a preferred embodiment the reaction can be carried out in two steps.Firstly a compound according to formula (1), or salt thereof, wherein R1is hydrogen is reacted to obtain a compound according to formula (1), orsalt thereof, wherein R1 is a nitrogen protecting group, as definedabove. Secondly, a compound according to formula (1), or salt thereof,wherein R1 is a nitrogen protecting group, as defined above, is reactedto obtain a compound according to formula (2), or salt thereof, whereinR1 is a nitrogen protecting group, as defined above.

Alternatively, the compound according to formula (1), or salt thereof,wherein R1 is hydrogen can be reacted directly, e.g. in the presence ofsec-BuLi as base and methyl iodide as methylating agent, to obtain acompound according to formula (2), or salt thereof, wherein R1 ishydrogen.

The compound according to formula (2), or salt thereof, wherein R1 is anitrogen protecting group, as defined above, can either be deprotected(i.e. the protecting group is removed so that R1 is hydrogen) ordirectly converted into a compound according to formula (3), or saltthereof, wherein R1 and R2 are independently, of each other, hydrogen ora nitrogen protecting group, as defined above, and R3 is hydrogen oralkyl. (This reaction is explained in detail below in subsection B-2.)The deprotected compound according to formula (2) (i.e. wherein R1 ishydrogen), or salt thereof, can also be reacted to obtain a compoundaccording to formula (3), or salt thereof, as detailed below, wherein R1and R2 are independently, of each other, hydrogen or a nitrogenprotecting group, as defined above, and R3 is hydrogen or alkyl.

The above-described reaction routes are shown in reaction Scheme 1,wherein “PG” means nitrogen protecting group, as defined above,preferably benzyl, benzyloxycarbonyl (Cbz), triethylsilyl (TES),trimethylsilyethoxymethyl (SEM), t-butoxycarbonyl (BOC),pyrrolidinylmethyl and pivaloyl, more preferably benzyl,trimethylsilyethoxymethyl, pyrrolidinylmethyl and pivaloyl, mostpreferably pivaloyl or t-butoxycarbonyl (BOC):

In another embodiment, the present invention relates to the completereaction sequence described in Scheme 1, and it also relates to each ofthe reaction steps. In still another embodiment, the present inventionrelates to the product obtained according to the complete reactionsequence described in Scheme 1, and it also relates to the productobtained according to each of the reaction steps shown in Scheme 1.

If an embodiment requires the removal of the nitrogen protecting group,as defined above, the removal usually can be carried out by using knownmethods. Preferably, the nitrogen protecting group, as defined above, isremoved by using acidic or basic conditions. Examples for acidicconditions are hydrochloric acid, trifluoroacetic acid, sulphuric acid.Examples of basic conditions are lithium hydroxide, sodium ethoxide.Nucleophiles such as sodium borohydride can be used.

In the case of N-benzyl as nitrogen protecting group it can be removedby hydrogenation or by the use of some suitable oxidising agents, e.g.ceric ammonium nitrate (CAN) or 2,3-dichloro-5,6-dicyano-p-benzoquinone(DDQ).

In another preferred embodiment, a compound according to formula (1″),or salt thereof, wherein R7, R8 and R9 are as defined above, ismethylated to obtain a compound according to formula (2), or saltthereof, wherein R1 is hydrogen, as shown in Scheme 2. Compounds offormula (1″), or salts thereof, can be prepared from compounds offormula (1), or salts thereof, according to methods well known in theart, as described e.g. in relevant chapters of standard reference workssuch as J. F. W. McOmie, “Protective Groups in Organic Chemistry”,Plenum Press, London and New York 1973 and in T. W. Greene and P. G. M.Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley,New York 1999.

The methylation reaction is carried out in the presence of a methylatingagent (eg. MeX). Preferred methylating agents are as described above.Furthermore, the reaction is preferably carried out in the presence of afluoride source.

Preferred fluoride sources are alkali or earth alkali metal fluoridesalts (e.g. LiF, CaF₂, CsF, KF) or other fluoride salts, e.g.tetrabutylammoniumfluoride (TBAF). The fluoride source can be usedcatalytically or stoichiometrically. Preferably, potassium fluoride orTBAF are used, in particular in catalytic amounts.

In a preferred embodiment the conversion of a compound of formula (1″)into a compound of formula (2) can be achieved by a two step process,namely, reaction of (1″) with a methylating agent followed by reactionof the resulting methylated product with a fluoride source (eg. alkalior earth alkali metal fluoride salt, such as LiF, CaF₂, CsF and KF, orother fluoride salts such as TBAF).

Using a compound according formula (1″), or salt thereof, as startingmaterial may have the advantage that a separate protection of theN-group is avoided, since the N-silyl group can be removed in situ underthe above described methylation reaction conditions.

The stereochemistry of the above reactions, shown in Schemes 1 and 2,might be of interest. In a preferred embodiment, the compound of formula(1), or salt thereof, in Scheme 1 is characterized in that theconfiguration is according to formula (1-a), (S-enantiomer).Analogously, in a preferred embodiment, the compound of formula (1″), orsalt thereof, in Scheme 2 is characterized in that the configuration isaccording to formula (1″-a), (S-enantiomer).

If a compound according to formula (1-a), or salt thereof, is used asstarting material, two compounds according to formula (2), or saltsthereof, can be obtained, namely two diastereomers according to formulae(2-a) and (2-b), or salts thereof,

wherein R1 is hydrogen or an above-described nitrogen protecting group.Likewise, If a compound according to formula (1″-a), or salt thereof, isused as starting material, two compounds according to formula (2), orsalts thereof, can be obtained, namely two diastereomers according toformulae (2-a) and (2-b), or salts thereof, wherein R1 is hydrogen. In apreferred embodiment, a compound of formula (2) or (3), or saltsthereof, in Scheme 1 is of formula (2-a) or (3-a), respectively. In alsoa preferred embodiment, a compound of formula (1″) or (2), or saltsthereof, in Scheme 2 is of formula (1″-a) or (2-a), respectively.

The diastereomeric ratio achieved is dependent on the chosen reactionconditions, particularly on the nitrogen protecting group and on thebase used. In a preferred embodiment a compound according to formula(2-a) is produced. In particular, a compound according to formula (1-a)is used as starting material and a compound according to formula (2-a)is produced in a diastereomeric ratio of more than 60:40, preferablymore than 70:30, particularly preferred more than 80:20. More preferredthe diastereomeric ratio is more than 90:10. The diastereomeric ratiocan be up to 99:1, preferably 100:0.

It has been found that by employing a process according to the presentinvention, the alkylation of a compound of formula (1), or salt thereof,can be achieved in high diastereoselectivity. The process of the presentinvention provides means to obtain the compound of formula (2), or saltthereof, with high diastereoselectivity, by reacting a compound offormula (1) with a base, as described above, and a methylating agent, asdescribed above. In particular, the methylation of a compound of formula(1-a), according to this embodiment, provides the compound of formula(2), wherein the ratio of diastereomers (2-a) to (2-b) is at least80:20, more preferably at least 85:15, yet more preferably at least91:9. In an embodiment of this preferred methylation reaction, the baseis, for example, RcRdNM, wherein Rc and Rd are independently selectedfrom alkyl, cycloalkyl, heterocyclyl or silyl and M is an alkali metalsuch as Na, Li or K. Preferred bases are lithium diisopropylamide,lithium dicyclohexylamine, lithium tetramethylpiperidine, lithiumbis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide; morepreferably lithium tetramethylpiperidine and potassiumbis(trimethylsilyl)amide. The methylating agent is preferablydimethylsulfate, methyl iodide or methyl bromide, preferably methyliodide or dimethylsulfate, more preferably dimethylsulfate. Preferably,the methylation is carried out at a temperature between a −78° C. and20° C., preferably between −10° C. and 20° C., more preferably between−10° C. and 0° C. It has been surprisingly found, the methylationreaction proceeds in high diastereoselectivity and with high yield at 0°C. The methylation is usually carried out in a solvent, as describedabove, preferably tetrahydrofuran, toluene or mixtures thereof.

In a further embodiment, the methylation of the compound of formula (1)or (1″), preferably of formula (1-a) or (1′-a), or salts thereof, with abase, as described above, and a methylating agent, as described above,can lead to a compound of formula (2″), preferably of formula (2″-a), orsalts thereof,

wherein R1 is hydrogen or a nitrogen protecting group, as defined above.

In a still further embodiment, a compound of formula (2″), preferably offormula (2″-a), or salts thereof, wherein R1 is hydrogen or a nitrogenprotecting group, as defined above, can also be prepared by treating thecompound of formula (2), preferably of formula (2-a), or salts thereof,wherein R1 is hydrogen or a nitrogen protecting group, with a base, asdescribed above, and a methylating agent, as described above.

Compounds according to formula (2-a), or salts thereof, can be obtainedas crystalline solids. Preferably, R1 is pivaloyl or t-butoxycarbonyl,more preferably R1 is pivaloyl. Optionally, compounds according toformula (2-a), or salts thereof, can be purified by crystallisation.

In a preferred embodiment the yield of the desired isomer can beenhanced. In this embodiment reaction steps according to Scheme 3 arecarried out. In one embodiment according to Scheme 3, when R1 is PG itis preferably pivaloyl or t-butoxycarbonyl.

In another embodiment, the present invention relates to the completereaction sequence described in Scheme 3, and it also relates to each ofthe reaction steps. In still another embodiment, the present inventionrelates to the product obtained according to the complete reactionsequence described in Scheme 3, and it also relates to the productobtained according to each of the reaction steps shown in Scheme 3.

In Scheme 3 “PG” means an above defined nitrogen protecting group. R10is any group which can be suitably saponified and/or decarboxylated.Preferably, R10 is —O-alkyl, or —O-aryl in particular —O-Et, —O-phenylor is —O-alkylaryl such as —O-benzyl; preferably R10 is —O-Et or—O-phenyl. For each one of the reactions of Scheme 3 preferably thefollowing reaction conditions are used:

(a): Treatment with a base (e.g. NaH, NaHMDS or KHMDS, preferably NaH orNaHMDS) and then with a further reagent that, after eliminating aleaving group, provides a —C(═O)— group, for example a —C(═O)OR groupwherein R is alkyl or aryl or alkylaryl; preferably alkyl or aryl. Suchfurther reagents are preferably carbonates of the formula (RO)(R′O)CO orcompounds of the formula XCOOR, wherein R and R′ independently, of eachother, are alkyl, aryl or arylalkyl, preferably alkyl or aryl andwherein X is halogen in particular chloride; preferred further reagentsof the formulae (RO)(R′O)CO or XCOOR are (MeO)₂CO, (EtO)₂CO, (BnO)₂CO,ClCO₂Me, ClCO₂Et, ClCO₂Bn; most preferably the further reagent is(MeO)₂CO, (EtO)₂CO, ClCO₂Me or ClCO₂Et;(b): Treatment with a base, preferably as described in step (a) and amethylating agent as described above;(c): Treatment with a saponification reagent (such as base), e.g. sodiumhydroxide, or treatment under hydrogenation conditions, e.g. Pd/C andhydrogen; preferably treatment with a saponification reagent. If undersuch saponification reaction conditions there is simultaneousdeprotection of nitrogen, compounds according to the formula (20-a)wherein R1=H are formed. If desired, before step (d), re-protection ofthe nitrogen such that R1=PG can be performed. Re-protection can be doneon treatment with a suitable nitrogen protecting agent, as definedabove, whereby PG can be the same or different from the original PGused;(d): Treatment under decarboxylation reaction conditions, e.g. heating,preferably in the presence of a solvent, more preferably initiated byboiling;(e): Treatment with a suitable nitrogen de-protecting agent, preferablyamine de-protecting agent, for example treatment with an acid or a base,preferably treatment with p-toluene sulfonic acid; or treatment with asuitable nitrogen protecting agent, preferably amine protecting agent,as defined above, to protect the N with a protecting group PG, which canbe the same or different from the original PG used. Step (e) isoptional.(f): Treatment under decarboxylation reaction conditions, e.g. heating,preferably in the presence of a solvent, more preferably initiated byboiling, optionally in the presence of a base, for example as describedfor compound 3c in Scheme 3 in Org. Lett., 2004, 6(25), 4727

The decarboxylation step (d) provides means to obtain the compound offormula (2), or salt thereof, in a diastereoselective manner. In oneembodiment, the decarboxylation of the compound of formula (20-a),wherein R1 is hydrogen or a nitrogen protecting group, preferablypivaloyl, and R11 is methyl, provides the compound of formula (2),wherein R1 is hydrogen or a nitrogen protecting group, preferablypivaloyl, in a ratio of diasteromers (2-a) to (2-b) of at least 55:45.In another embodiment, the decarboxylation of the compound of formula(20-a), wherein R1 is hydrogen or a nitrogen protecting group,preferably hydrogen, and R11 is methyl, provides the compound of formula(2), wherein R1 is hydrogen or a nitrogen protecting group, preferablyhydrogen, in a ratio of diasteromers (2-a) to (2-b) of at least 29:79.

The decarboxylation step (f) can also provide means to obtain thecompound of formula (2), wherein R1 is hydrogen or a nitrogen protectinggroup, or salt thereof, with diastereoselectivity.

In a preferred embodiment compounds of formula (2) obtained upon steps(d), (e) or (f), in Scheme 3, are according to formula (2-a). In anotherpreferred embodiment for step (d) R is pivaloyl or hydrogen. In yetanother preferred embodiment R1 is a nitrogen protecting group forcompounds of formula (20-a) and/or (2).

Steps (c) or (d) can be performed, for example, as described in Org.Biomol. Chem 2007, 5, 143 and in Org. Lett. 2003, 5, 353.

Subsection B-2: Reacting the Methylated Lactam According to Formula (2)to Obtain an Intermediate According to Formula (3)

Another subject of the present invention is a process for producing acompound according to formula (3) or a salt thereof

wherein R1 and R2 are independently, of each other, hydrogen or anitrogen protecting group, as defined above, and R3 is hydrogen oralkyl, comprising reacting a compound according to formula (2), or saltthereof,

wherein R1 is hydrogen or a nitrogen protecting group, as defined above,with a ring opening agent, as defined below. In a preferred embodiment,R1 and R2 are hydrogen and R3 is an ethyl group.

Alternatively, in formula (3), or salt thereof, R1 and R2 along with theN atom to which they are attached to can together form a cyclic ringstructure, preferably a five-membered ring (and thus form a bifunctionalcyclic nitrogen protecting group, which together with said N atomresults, for example, in a five-membered ring succinimide- or maleimidestructure). The compound according to formula (2), or salt thereof, ispreferably obtained by a reaction as described above in subsection B-1.

In formula (3), or salt thereof, preferably R1 is hydrogen or a nitrogenprotecting group as defined above and R2 is hydrogen. Furthermore, R3 ispreferably hydrogen or ethyl.

Generally, following the above-described methylation reaction, acompound of formula (2) or salt thereof, preferably a compound offormula (2-a) or salt thereof, can be reacted with a ring opening agentto yield a compound of formula (3) or salt thereof. The lactam ringopening reaction can occur under basic, neutral or acidic conditions.Examples for ring opening agents are nucleophilic bases such as alkalimetal hydroxides (for example sodium hydroxide or lithium hydroxide) orneutral compounds such as hydrogenperoxides (such as lithiumhydrogenperoxide). Further examples are Lewis or BrØnsted acids,preferably in the presence of water. Preferred acids are mineral acidssuch as sulphuric, perchloric and hydrochloric acid. Sulphonic acidssuch as para-toluenesulphonic acid are also suitable as arepolymer-bound acids such as Amberlyst®. Especially hydrochloric acid isused as a ring opening agent.

The ring opening agent can be used catalytically or stoichiometrically.Preferably, the ring opening agent is used in an amount from 1 to 10equivalents.

Compounds according to formula (3) can exist as salts, for example ascarboxylate salts or as acid addition salts. Acid addition salts arepreferred. Generally, various acids are suitable to produce an acidaddition salt. Preferred are mineral acids, in particular sulfuric acid,hydrochloric acid, hydrobromic acid or perchloric acid. Sulphonic acidssuch as para-toluenesulphonic acid are also suitable. Especiallyhydrochloric acid is used. Alternatively, compounds according to formula(3) can also exist as the free base (zwitterions).

The ring opening reaction can be performed at a wide temperature range,e.g. between −10° C. and +150° C. Preferably, the reaction is carriedout between +20° C. and +125° C. The reaction can be carried out in avariety of solvents e.g. water, or ethanol or mixtures of these.Additional solvents such as toluene, isopropyl acetate, tetrahydrofuranor tert-butylmethylether can be used, Preferably, ethanol and/or wateris used.

In a preferred embodiment the ring opening reaction is carried out suchthat a compound having a configuration according to formula (3-a) or asalt thereof is obtained

wherein R1 and R2 are independently, of each other, hydrogen or anitrogen protecting group, as defined above, and R3 is hydrogen oralkyl. In a preferred embodiment, R1 and R2 are hydrogen and R3 isethyl. The compound according to formula (3-a), or salt thereof, can beobtained if a compound according to formula (2-a), or salt thereof, isused as starting material.

The compound according to formula (3-a), or salt thereof, is theso-called 2R,4S-diastereoisomer. Alternatively, also the2R,4R-diastereoisomer, 2S,4S-diastereoisomer and 2S,4R-diastereoisomercan be produced.

The reaction from compound (2), or salt thereof, to compound (3), orsalt thereof, can be carried out in various embodiments. For example, acompound according to formula (2), or salt thereof, wherein R1 ishydrogen can be used as starting material. Also a compound according toformula (2), or salt thereof, wherein R1 is a nitrogen protecting group,as defined above, preferably a pivaloyl group or a BOC group. If acompound according to formula (2), or salt thereof, wherein R1 is anitrogen protecting group, as defined above, is used as startingmaterial, preferably the nitrogen protecting group is removed during thering opening reaction. This means that preferably a compound accordingto formula (3), or salt thereof, wherein R1 and R2 are hydrogen, isobtained.

If desired, a compound of formula (3), or salt thereof, wherein R1 andR2 are hydrogen can be converted again into a compound of formula (3),or salt thereof, wherein either R1 and/or R2 are, independently of eachother, a nitrogen protecting group, as defined above. This might be thecase if R3 of formula (3) should be changed from a hydrogen atom into analkyl residue. In Scheme 4 below preferred embodiments are exemplified.

In another embodiment, the present invention relates to the completereaction sequences described in Scheme 4 converting the compound offormula (2-a), as defined herein, into the compound of formula (3-a), asdefine herein, and it also relates to each of the reaction steps. Instill another embodiment, the present invention relates to the productobtained according to the complete reaction sequence described in Scheme4, and it also relates to the product obtained according to each of thereaction steps shown in Scheme 4.

In Scheme 4 “PG1” is a nitrogen protecting group, as defined above,preferably pivaloyl. “PG2” is also a nitrogen protecting group, asdefined above, preferably different from PG1, in particular BOC. “Alk”is an alkyl group, preferably ethyl. The term “.HX” indicates that thecompound is preferably present as an acid addition salt, especially inform of HCl.

The reactions shown in Scheme 4 are not limited to the specificstereochemistry disclosed. Contrary, they can also be carried out withcompounds having any other possible configuration.

Generally, the reactions (a) to (j) can be carried out under variousconditions. Preferred conditions for each one of the reactions (a) to(j) of Scheme 4 are given below.

-   (a): Treatment with a suitable nitrogen de-protecting agent,    preferably amine de-protecting agent, for example treatment with an    acid or a base, preferably treatment with p-toluene sulfonic acid;-   (b): Treatment with the above-described ring opening agents,    preferably with hydrochloric acid or a mixture of acetic acid and    hydrochloric acid;-   (c): Treatment with a suitable nitrogen protecting agent, preferably    amine protecting agent, more preferably with    di-tert-butyl-dicarbonate;-   (d): Treatment with an aliphatic alcohol, preferably ethanol.    Optionally in the presence of thionyl chloride or an acid, such as a    mineral acid, for example HCl, H₂SO₄, H₃PO₄ or HBr; preferably    optionally in the presence of thionyl chloride. Optionally, when PG1    or PG2 are acid labile, this step can include treatment with a    suitable alkylating reagent, for example, an alkyl halide (such as    ethyl chloride, ethyl bromide or ethyl iodide, preferably ethyl    iodide) in the presence of a base (eg NaH, Cs₂CO₃).-   (e): Treatment with acid or base in the presence of water,    preferably hydrochloric acid in water. This step can include further    treatment with a suitable nitrogen de-protecting agent, for example    Pd/C and hydrogen, when PG1 is neither acid not base labile    N-protecting group. Treatment with acid or base in the presence of    water is preferred;-   (f): Treatment with suitable nitrogen protecting agent, preferably    amine protecting agent, more preferably with BOC;-   (g): Treatment with a ring opening agent, as described above,    preferably lithium hydroxide;-   (h): Treatment with acid or base in alcoholic solution, preferably    hydrochloric acid in ethanol;-   (i): Treatment with acid or base in alcoholic solution, preferably    hydrochloric acid in ethanol;-   (j): Treatment with a ring opening agent, as described above,    preferably lithium hydroxide; optionally, when PG1 is a base labile    N-protecting group, this step can further include further treatment    with a suitable nitrogen protecting agent, which can be the same or    different from the original PG1 used;-   (k): Treatment with a suitable nitrogen protecting agent, as defined    above, preferably amine protecting agent, preferably in the presence    of a base, such as triethylamine; or treatment with a suitable    nitrogen de-protecting agent, preferably amine de-protecting agent,    for example treatment with Pd/C and hydrogen or treatment with a    base. Step (k) is optional.

The protecting group preferably changes in the reaction routes (a)/(f)and (e)/(c), e.g. from PG1 to PG2. The protecting group preferably doesnot change in the reaction route (j).

In a preferred embodiment, R1 and R2 are H for the compound of formula(3-a) shown in Scheme 4.

It is preferred that reactions (d), (h) and (i) of Scheme 4 lead to acompound, wherein “Alk” is ethyl. Said compound is preferably used inthe production of an NEP-inhibitor as described below in subsection B-3.

In a further aspect, the present invention relates to step (d),preferably wherein a compound of formula (3-a), wherein R1 and R3 are Hand R2 is a nitrogen protecting group, preferably an acid labilenitrogen protecting group such as BOC, is converted into the compound offormula (3-a), or salt thereof, wherein R1 and R2 are H and R3 is alkyl,preferably ethyl, by treatment with thionyl chloride and an aliphaticalcohol, preferably ethanol. In a preferred embodiment, the compound offormula (3-a), obtained according to this process, wherein R1 and R2 areH and R3 is alkyl, is (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoicacid ethyl ester, or salt thereof.

Scheme 4 encompasses the preferred absolute configuration of compoundsof formulae (2) and (3). However, the present invention also relates tothe complete reaction sequences and to each of the reaction steps,wherein any of the compounds (product or starting material) is a purediastereomer, or mixture thereof, or enantiomer, or mixtures thereof,e.g., mixtures of enantiomers, such as racemates. In a preferredembodiment, step (d) provides a method to prepare a compound of formula(3), preferably wherein R1 and R2 are H and R3 is ethyl, or saltthereof, in a diastereomeric ratio of (3-a) to (3-b) of at least 60:40,preferably of at least 70:30, more preferably of at least 80:20, yetmore preferably of at least 90:10, most preferably of at least 99:1.

Subsection B-3: Reacting the Intermediate (3) to Obtain a NEP-Inhibitoror Prodrug Thereof, Preferably an NEP-Inhibitor Prodrug According toFormula (18)

The compound according to formula (3), or salt thereof, especially thecompound according to formula (3-a), or salt thereof, can be used in theproduction of an NEP-inhibitor or prodrug thereof.

The term “NEP inhibitor” describes a compound which inhibits theactivity of the enzyme neutral endopeptidase (NEP, EC 3.4.24.11) and itis understood to include salts thereof.

The term “prodrug” describes a pharmacological substance which isadministered in an inactive (or less active) form. Once administered,the prodrug is metabolised in the body in vivo into the active compound.

Therefore, an embodiment of the process of the present inventioncomprises one or more additional steps wherein the compound according toformula (1) is further reacted to obtain an NEP-inhibitor or a prodrugthereof.

In the present invention the terms “NEP-inhibitor” or “NEP-inhibitorprodrug” relates to the substances as such or to salts thereof,preferably pharmaceutically acceptable salts thereof. Examples aresodium, potassium, magnesium, calcium or ammonium salts. Calcium saltsare preferred.

Preferably compounds according to formula (1-a), or salts thereof, arefurther reacted to obtain a NEP-inhibitor or a prodrug thereof.Particularly preferred is a compound according to formula (3-a), or saltthereof, wherein R1 and R2 are hydrogen and R3 is ethyl.

In a preferred embodiment a compound according to formula (3-a) isfurther reacted to obtain the NEP inhibitor prodrugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester, or salt thereof, according to formula (18) (known inthe art as AHU 377) or a salt thereof.

Hence, another object of the present invention is a process forproducing a compound according to formula (18) or a salt thereof.

comprising the steps

-   a) providing a compound according to formula (1-a), or salt thereof,

-   b) methylating the compound according to formula (1-a), or salt    thereof, to obtain a compound according to formula (2-a), or salt    thereof,

-   c) reacting the compound according to formula (2-a), or salt    thereof, with a ring opening agent to obtain a compound according to    formula (3-a) or a salt thereof

-   d) reacting a compound according to formula (3-a) or a salt thereof    to obtain a compound according to formula (18) or a salt thereof,    -   wherein in the above formulae R1 and R2 are independently, of        each other, hydrogen or a nitrogen protecting group, as defined        above, and R3 is hydrogen or alkyl.

In another embodiment, the present invention relates to the aboveprocess comprising the steps (a) to (d) and it also relates to each ofthe reaction steps (a) to (d). In still another embodiment, the presentinvention also relates to the product obtained according to each of thereaction steps (a) to (d) and to the product obtained according to thecomplete reaction sequence (a) to (d).

The reactions from compound (1-a), or salt thereof, to (2-a), or saltthereof, and from compound (2-a), or salt thereof, to (3-a), or saltthereof, are described above in the previous subsections B-1 and B-2,respectively.

Generally, the present invention comprises any pharmaceuticallyacceptable salt ofN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methyl-butanoicacid ethyl ester, wherein the calcium salt is preferred.

The NEP inhibitor prodrugN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester, or salt thereof, optionally is further reacted toobtain the active NEP inhibitorN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid, or salt thereof.

In a preferred embodiment of the present invention the synthesis ofN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester, or salt thereof, is carried out according to Scheme 5:

Generally, reactions (a) to (c) can be carried out under variousconditions. Steps (b) and (c), which provide, respectively, thecorresponding sodium and calcium salts thereof, are optional steps.Preferred conditions for each of the reactions (a) to (c) of Scheme 5are given below.

(a): Treatment with succinic anhydride, preferably in the presence of abase. Preferred bases are triethylamine, pyridine, sodium carbonate,sodium hydrogen carbonate and potassium carbonate; more preferably thebase is triethylamine;

(b): Treatment with a sodium base, preferably NaOH

(c): Treatment with a calcium salt, preferably CaCl₂.

In a preferred embodiment, the starting material for the synthesis ofN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoicacid ethyl ester, or salt thereof, according to Scheme 5, is in the formof an acid addition salt HX, preferably HCl. In this preferredembodiment, step (a) according to Scheme 5 requires a base, such astriethylamine, pyridine, sodium carbonate, sodium hydrogen carbonate orpotassium carbonate, preferably the base is triethylamine.

Section C: Preparation Methods For The Key Lactam (1)

The present invention comprises seven methods for preparing the KeyLactam (1), or salt thereof, which are described below in subsectionsC-1 to C-7.

Subsection C-1: Method 1

In one embodiment, the subject of the present invention is a process forpreparing a compound according to formula (1), or salt thereof,

wherein R1 is as defined above,comprising the following steps:

-   a) providing a compound according to formula (4), or salt thereof,

-   -   wherein R1 is hydrogen or a nitrogen protecting group, as        defined above, and R4 is an CO-activating group, as defined        below,

-   b) reacting the compound according to formula (4), or salt thereof,    with a biphenylic compound to obtain a compound according to formula    (5)

-   -   wherein R1 is hydrogen or a nitrogen protecting group, as        defined above, and

-   c) reduction, for example by hydrogenation or by using a reducing    agent known in the art (e.g. a hydride reagent such as sodium    borohydride), preferably by hydrogenation, of a compound according    to formula (5), or salt thereof, to obtain a compound according to    formula (1), or salt thereof.

In another embodiment, the present invention relates to the aboveprocess comprising the steps (a) to (c) and it also relates to each ofthe reaction steps (a) to (c). In still another embodiment, the presentinvention also relates to the product obtained according to each of thereaction steps (a) to (c) and to the product obtained according to thecomplete reaction sequence (a) to (c).

Explanations Regarding Step (4)→(5):

Compounds according to formula (4), or salts thereof, are readilyavailable from glutamic acid and/or pyroglutamic acid or derivativesthereof, i.e. from the chiral pool.

In formula (4) R4 is a CO-activating group. A suitable CO-activatinggroup generally is any group which can act as a leaving group. Examplesof groups which can act as a CO-activating group are —NR₂, —OR, —SR orhalogen, wherein R is hydrogen or (optionally substituted) alkyl or(optionally substituted) aryl.

Preferably, the following groups are suitable as CO-activating group R4in formula (4):

-   a) R4 can be an amino group, in particular, —NR12R13, wherein R12    and R13 are    -   independently selected from the group consisting of alkyl,        alkoxy, aryl, aryloxy, arylalkyl and arylalkoxy; preferably R12        is alkyl (eg methyl) and R13 is selected from the group        consisting of alkoxy (eg. methoxy or ethoxy), aryloxy (eg.        phenyloxy) and arylalkoxy (eg, benzyloxy); or    -   together are unsubstituted or substituted alkylene or        unsubstituted or substituted alkenylene; for example        piperidinyl, morpholinyl, 1-alkylpiperazinyl (for example        1-methylpiperazinyl), 2-, 3-, 4-alkylpiperidinyl,        1,2,3,6-tetrahydropyridinyl, pyrrolidinyl or imidazolyl; or    -   R12 is alkyl (eg. methyl) and R13 is —X—R14, wherein X is S and        R14 is alkyl (eg. methyl or ethyl), aryl (eg. phenyl) or        arylalkyl (eg. benzyl); or    -   R12 is alkyl (eg. methyl) and R13 is —NRaRb, wherein Ra and Rb        are independently selected from alkyl (eg. methyl or ethyl),        aryl (eg. phenyl) or arylalkyl (eg. benzyl).

Preferred R4 is a dialkylated amino group, which can be cyclic (e.g.morpholinyl or imidazolyl) or acyclic (eg. dimethylamino). Cyclic aminogroups preferably comprise a 5-member or 6-member ring, with or withoutadditional substitution, in particular substitution refers to one ormore substituents selected from the group consisting of halo, alkyl,alkoxy, aryl, aryloxy, arylalkyl and arylalkoxy. Also suitable arealkylaryl amino groups (e.g. phenylmethylamino) or diaryl amino groups(e.g. diphenylamino). Further suitable are so-called Weinreb derivatives(i.e. derivatives of methylmethoxyamine), in particular —NR12R13,wherein R12 is methyl or methoxy and R13 is independently selected fromalkyl, alkoxy, aryl, aryloxy, arylalkyl or arylalkoxy. Further suitableare amino groups possessing an alkyl/aryl group and a coordinatinggroup, e.g. alkoxy, alkylthio.

-   b) R4 can be a group having the formula —X—R, wherein X is O or S    and R is alkyl or aryl. Furthermore, R4 can be a group having the    formula —O—CO—R, wherein R is alkyl or aryl.-   c) R4 can be a halo, preferably chloro.-   d) R4 can be —O—R15 wherein R15 is —NR12R13, as defined above, or    R15 is unsubstituted or substituted heterocyclyl.

Preferably, the CO-activating group is selected from dimethylamino,morpholinyl, imidazolyl, methylmethoxyamino, —O-methyl, —O-ethyl,chloro, bromo, pivaloyl and acetyl. In particular the CO-activatinggroup is morpholine.

If the CO-activating group is chosen from the above groups a) or b) informula (4), the residue R1 is preferably a nitrogen protecting group,as defined above, or alternatively hydrogen. If the CO-activating groupis chosen from the above group c) in formula (4), the residue R1 ispreferably hydrogen.

The compound according to formula (4), or salt thereof, is reacted witha biphenylic compound.

In a preferred embodiment the biphenylic compound can be activated. Asuitable method for the activation is the preparation of anorganometallic complex comprising a biphenyl ligand.

Preferred Activated Biphenylic Compounds are:

Biphenylmagnesium halide or di(biphenyl)magnesium (Grignard reagents).Suitable halides generally are chloride, bromide and iodide, whereinbromide is especially preferred.

Further examples for activated biphenylic compounds are biphenyllithium,biphenylcuprate (low and higher-order cuprates) and biphenylzinc. Thosecompounds can be used individually or in the presence of another metal,e.g. copper, zinc, palladium, platinum, iron, iridium or ruthenium.

Generally, 2.0 to 2.5 equivalents of biphenylmagnesium halide ordi(biphenyl)magnesium are used. In an embodiment initial deprotonationof the N—H group with, for example, another Grignard reagent (e.g.isopropylmagnesium chloride) or a base (e.g. sodium hydride) may beperformed before addition of the activated biphenylic compound to reducethe required amount of biphenylmagnesium halide ordi(biphenyl)magnesium. In this embodiment, 0.7 to 1.5 equivalents,preferably 1.0 to 1.25 equivalents are used.

Generally, there are two preferred embodiments to carry out theabove-mentioned reaction:

-   1) Reacting a compound according to formula (4), or salt thereof,    wherein R4 (the CO-activating group) is chosen from the above    groups a) or b). In this case, an activated (e.g. metallated)    biphenylic compound is preferably used, in particular a    biphenylmagnesium halide is used.-   2) Reacting a compound according to formula (4), or salt thereof,    wherein R4 (the CO-activating group) is chosen from the above group    c). In this case, biphenyl is preferably used as biphenylic    compound. The reaction is preferably carried out in the presence of    a suitable Lewis acid, e.g. aluminium trichloride. Alternatively,    the biphenylic compound may be activated with a suitable functional    group (for example para-silyl) to allow for milder conditions to be    used during the Friedel-Crafts acylation. Furthermore, reference is    made to the Friedel Crafts' method described in J. Am. Chem. Soc.,    Vol 103, No. 20, 1981, 6157.

Hence, it is preferred that R4 of formula (4) is morpholinyl and thebiphenylic compound used in step b) is a biphenylmagnesium halide,

or

R4 of formula (4) is chloride and the biphenlyic compound used in stepb) is biphenyl.

The embodiments 1) and 2) are exemplified in Scheme 6 below.

Explanations Regarding Step (5)→(1):

The reduction of the carbonyl group of a compound according to formula(5), or salt thereof, for example by hydrogenation or by using areducing agent known in the art (e.g. a hydride reagent such as sodiumborohydride) forms a compound according to formula (1) or salt thereof.Preferably the reduction of a compound according to formula (5), or saltthereof, is accomplished by hydrogenation. Depending on reactionconditions, the reaction can be carried out directly, or via thecorresponding alcohol according to formula (13), or salt thereof, asintermediate

wherein R1 is hydrogen or a nitrogen protecting group, as defined above.

Complete reduction of the carbonyl group (i.e. reaction (5)→(1)) can beachieved using a hydrogenation catalyst, such as palladium on carbon(hereinafter referred to as Pd/C). This can be done in the presence orabsence of an acid. Preferred is Pd/C selected from the group consistingof 10% Pd/C type K-0218 (commercially available from Heraeus GmbH), 10%type PD CP 4505 D/R (commercially available from BASF), 5% Pd/C type 39,10% Pd/C type 39, 10% Pd/C type 39 (7200), 20% Pd/C type 91, 10% Pd/Ctype 338, 10% Pd/C type 394, 10% Pd/C type 394 (6065), 10% Pd/C type 394(6249), 10% Pd/C type 395, 10% Pd/C type 395 (6002), 10% Pd/C type mod(72595), 15% Pd/C type A101023 and 15% Pd/C type A502085 (which arecommercially available from Johnson Matthey); more preferably 10% Pd/Ctype 338, 10% Pd/C Mod (72595), 10% Pd/C type 39, 10% Pd/C type 394(6065) and 10% Pd/C type 395; most preferably 10% Pd/C type 39 and 10%Pd/C type 394 (6065).

In one embodiment, the hydrogenation usually is carried out at atemperature between 0° C. and 60° C., preferably between 20° C. and 50°C. The applied hydrogen pressure usually ranges between 1 bar and 30bar, preferably between 2 bar to 25 bar. The reaction time usuallyranges between 1 hour and 30 hours, preferably between 5 hours and 20hours.

In another embodiment, the hydrogenation usually is carried out at atemperature of from of 0° C. to 100° C., preferably of from 20° C. to80° C., more preferably of from 40° C. to 80° C., most preferably offrom 50° C. to 80° C.

Solvents generally known in the art can be used. Preferred solvents are,for example, isopropyl acetate, methyltetrahydrofuran, toluene or amonovalent alcohol., such as methanol or ethanol. More preferably,toluene is used. The amount of solvent employed may be such that theconcentration of substrate is in a the range of from 0.1 to 1.5 M,preferably of from 0.2 to 0.8 M.

The amount of hydrogenation catalyst to substrate, typically employed inthe process, may be in the range of from 1 to 30 wet wt %, preferably offrom 2 to 25 wet wt %, more preferably of from 5 to 20 wet wt %.

Depending on reaction conditions, the hydrogenation can be stopped atthe corresponding secondary alcohol (13) (as a mixture ofdiastereoisomers), which can then be isolated. Reduction of the carbonylto the alcohol generally can be achieved using reducing agents known inthe art (e.g. sodium borohydride). Conversion of the OH into a leavinggroup, such as halogen, by methods well-known to person skilled in theart, and subsequent treatment with a hydride reagent (for example withsodium borohydride or diisobutylaluminium hydride) would yield acompound according to formula (1). If required, the alcohol intermediateaccording to formula (13), or salt thereof, can also be obtained as asingle diastereoisomer (either R or S) by use of, for example, anenantioselective/diastereoselective hydrogenation catalyst, for exampleas described in Angew. Chem. Int. Ed 2001, 40, 40-73, in particular asdescribed in Scheme 36 therein.

In the reactions (4)→(5) and (5)→(1) the stereochemistry might beimportant. In a preferred embodiment the configuration of the compoundsof formulae (4), (5) and (1), or salts thereof, is according to formulae(4-a), (5-a) and (1-a)

wherein R1 is hydrogen or a nitrogen protecting group, as defined above,and R4 is an CO-activating group, as defined above.

If a secondary alcohol according to formula (13), or salt thereof, asintermediate is produced, it preferably has a configuration as shown informula (13-a)

wherein R1 is hydrogen or a nitrogen protecting group, as defined above.Subsection C-2: Method 2

In another embodiment, the subject of the present invention is a processfor preparing a compound according to formula (1), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, as defined above,comprising the following steps:

-   a) providing a compound according to formula (7), or salt thereof,

-   -   wherein R1 and R2 are independently, of each other, hydrogen or        a nitrogen protecting group, as defined above,

-   b) reacting a compound according to formula (7), or salt thereof, in    a Wittig reaction to obtain a compound according to formula (8), or    salt thereof,

wherein R1 and R2 are independently, of each other, hydrogen or anitrogen protecting group, as defined above, and R5 is hydrogen oralkyl,

-   c) reduction of a compound according to formula (8), or salt    thereof, to obtain a compound according to formula (9), or salt    thereof,

-   -   wherein R1 and R2 are independently, of each other, hydrogen or        a nitrogen protecting group, as defined above, and R5 is        hydrogen or alkyl,

-   d) optionally removing the nitrogen protecting groups, thereby    yielding a compound according to formula (10) or a salt thereof

-   -   wherein R5 is hydrogen or alkyl, and

-   e) reacting the compound according to formula (10) or (9), or salt    thereof, preferably reacting a compound of formula (10), under    ring-closing conditions to obtain a compound according to formula    (1), or salt thereof, wherein R1 is hydrogen or a nitrogen    protecting group, preferably R1 is hydrogen.

The present invention relates to the above process comprising the steps(a) to (e) and it also relates to each of the reaction steps (a) to (e).Moreover, the present invention also relates to the product obtainedaccording to each of the reaction steps (a) to (e) and to the productobtained according to the complete reaction sequence (a) to (e).

Optionally, upon reacting a compound according to formula (10), or saltthereof, under ring-closing conditions to obtain a compound according toformula (1), or salt thereof, wherein R1 is hydrogen, treatment with asuitable nitrogen protecting agent, as defined above, can follow toprovide a compound of formula (1) wherein R1 is a nitrogen protectinggroup.

In a preferred embodiment in formula (7) R1 is a nitrogen protectinggroup (as defined above in section A) and R2 is hydrogen. The sameapplies to formulae (8) and (9).

The compound according to formula (7), or salt thereof, is reacted in aWittig reaction to obtain a compound according to formula (8), or saltthereof. In the Wittig reaction usually the aldehyde according toformula (7), or salt thereof, is treated with a phosphorus ylide (alsocalled a phosphorane) to obtain the olefin of formula (8), or saltthereof. Phosphorus ylides are usually prepared by treatment of aphosphonium salt with a base and phosphonium salts are usually preparedfrom a phosphine and an alkyl halide, by methods well-known to theperson skill in the art.

In the present application preferably a compound according to formula(Ar)₃P═CH—CO₂—R is used in the Wittig reaction, wherein Ar is aryl and Ris alkyl. In particular, Ph₃P═CH—CO₂—C₂H₅ is used in the Wittigreaction.

The term “

” on olefins of the present application represents a covalent bond,which comprises an (E) stereoisomer as well as a (Z) stereoisomer of therespective olefin. Furthermore, mixtures of (E) and (Z) stereoisomersare also encompassed.

Furthermore, in formula (8) the residue R5 is hydrogen or alkyl.Preferably, R5 is C1-C6 alkyl, more preferably ethyl. The same appliesto formulae (9) and (10).

The double bond of the compound according to formula (8), or saltthereof, is hydrogenated to obtain a compound according to formula (9),or salt thereof.

Generally, the hydrogenation can be carried out by known methods.Preferably, the hydrogenation is carried out in the presence of Pd/C ascatalyst.

The hydrogenation usually is carried out at a temperature between 0° C.and 60° C., preferably between 20° C. and 50° C. The applied hydrogenpressure usually ranges between 1 bar and 30 bar, preferably between 2bar to 25 bar. The reaction time usually ranges between 1 hour and 30hours, preferably between 5 hours and 20 hours.

If at least one residue R1 or R2 of formula (9) is a nitrogen protectinggroup, as defined above, it can be removed in an optional reaction step,by methods well-known in the art, in particular as described inreference books above mentioned, in the relevant chapters thereof, toobtain a compound according to formula (10). If an embodiment requiresthe removal of the nitrogen protecting group, the removal usually can becarried out by using known methods. Preferably, the nitrogen protectinggroup is removed by using SOCl₂, hydrochloric acid, sulphuric acid ortrifluoroacetic acid. In the case of N-benzyl, as nitrogen protectinggroup, it can be removed by hydrogenation or some suitable oxidisingagents, e.g. ceric ammonium nitrate (CAN) or2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).

The compound according to formula (10), or salt thereof, is subjected toring-closing conditions to obtain a compound according to formula (1) orsalt thereof. Suitable ring closing conditions are those that employ abase. Preferred bases used are alkylamines or alkali metal alkoxides.Particularly preferred are triethylamine or sodium methoxide.

In the above reactions the stereochemistry might be of importance. In apreferred embodiment compounds, or salts thereof, are used having aconfiguration as shown in formula (7-a), (8-a), (9-a) and (10-a)

wherein in the above formulae R1, R2 and R5 are as defined above forformulae (7) to (10). Furthermore, preferably a compound according toformula (1-a), or salt thereof, as defined above, is obtained.

A preferred embodiment for the preparation of the Key Lactam (1), orsalt thereof, starting from the compound according to formula (7), orsalt thereof, is shown in Scheme 7 below.

In Scheme 7 “R1” is a nitrogen protecting group, preferably BOC.

In another embodiment, the present invention relates to the completereaction sequences described in Scheme 7 converting the compound offormula (7-a), as defined herein, into the compound of formula (1-a), asdefine herein, but it also relates to each of the reaction steps. Instill another embodiment, the present invention relates to the productobtained according to the complete reaction sequence described in Scheme7, but it also relates to the product obtained according to each of thereaction steps shown in Scheme 7.

Subsection C-3: Method 3

As an alternative to the reduction of the aryl ketone according toformula (5) that is formed in method 1, addition of a biphenyl anion toa sp^(a) hybridised leaving group, can be performed.

Hence, a further object of the present invention is a process forpreparing a compound according to formula (1), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, as defined above,comprising reacting a compound according to formula (11), or saltthereof,

wherein R1 is hydrogen or a nitrogen protecting group, as defined above,and R6 is a leaving group, as defined below, with an activated (e.g.metallated) biphenylic compound, preferably with a biphenylmagensiumhalide.

R1 can be a nitrogen protecting group as described above in section A:The Key Lactam (1), or salt thereof, as such. Preferably, R1 ishydrogen.

Generally, R6 is a suitable leaving group. Examples of suitable leavinggroups are amino, alkoxy (e.g. methoxy, ethoxy), carboxylate, halogen(e.g. fluoride, chloride, bromide, iodide), azide, thiocyanate, nitro,cyanide, tosylate, triflate and mesylate. Preferably, R6 is iodide,tosylate or mesylate.

Regarding the term “activated biphenylic compound” it is referred to theexplanations above for method 1 in subsection C-1. Preferably theactivated biphenylic compound is a biphenylmagnesium halide, especiallybiphenylmagnesium bromide.

The reaction can be carried out according to the following preferredembodiment, wherein R1 is hydrogen:

Starting from known pyroglutaminol (CAS#17342-08-4), the replacement ofthe alcohol with a leaving group (e.g. iodide [CAS#29266-73-7], tosylate[CAS#51693-17-5] or mesylate), according to well-known methods, forexample as described in Richard C. Larock, “Comprehensive OrganicTransformations: A Guide to Functional Group Preparations”, SecondEdition, Wiley-VCH Verlag GmbH, 2000, in particular as described in therelevant chapters thereof, yields a compound according to formula (11).The following addition of biphenylmagnesium halide, in particularbiphenylmagnesium bromide, (or an alternative metallated biphenyl, e.g.Li, Zn), optionally in the presence of another metal (e.g. copper, zinc,palladium) in either catalytic or stoichiometric amounts, yields thecompound according to formula (1).

In another embodiment, the coupling of the compound of formula (11), orsalt thereof, wherein R6 is a leaving group, preferably halo (such asbromo or iodo) or a tosylate or a mesylate group, with abiphenylmagnesium halide takes place under Fe- or Mn-catalyzed crosscoupling reaction conditions, for example by the use of FeCl₃, Fe(acac)₃or MnCl₂, as described, for example, in Angew. Chem. Int. Ed., 2004, 433955-3957, in Org. Lett., 2004, 6, 1297-1299, in Chem. Commun., 2004,2822-2823, in J. Am. Chem. Soc., 2004, 126, 3686-3687, in Synlett, 2001,1901-1903 or in Synthesis, 1998, 1199-1205. The Fe-catalyzed crosscoupling reaction conditions preferably takes place by the use of FeCl₃.

In still another embodiment, the coupling of the compound of formula(11), or salt thereof, wherein R6 is a leaving group, preferably halo(such as bromo or iodo) or a tosylate or a mesylate group, with abiphenylmagnesium halide takes place in the presence of a metal saltadditive, which is used in catalytic or stoichiometric amounts. A usefulmetal salt additive is, for example, a copper(I), copper(II), zinc(II),silver(I), cadmium(II), mercury(II), aluminum(III), gallium(III),indium(III), tin(IV), titanium(IV) or zirconium(IV) salt. Examples ofsuch salts are the corresponding chloride, bromide, iodide, carbonate,hydroxide, oxide, C₁-C₇-alkanoates such as the acetate and propionate,C₁-C₇-alkoxides such as the methoxide and ethoxide, trifluoroacetate,acetylacetonate, nitrate, cyanide, sulfate, trifluoromethanesulfonate,methanesulfonate, benzenesulfonate or para-toluenesulfonate. Preferredmetal salt additives are copper salts, such as copper cyanide, which ispreferably used in a stoichiometric amount.

Generally, the use of more than one equivalent of a Grignard reagent (orother metallated species) can be prevented by adding an additional base(eg isopropylmagnesium chloride or NaH) to remove the NH proton if R1 ishydrogen.

The stereochemistry of the reaction might be of interest. Preferably, acompound, or salt thereof, having a configuration according to formula(11-a) is used

wherein R1 and R6 are defined as above for compounds according toformula (11), or salts thereof. Furthermore, preferably a compoundaccording to formula (1-a), or salt thereof, is obtained.

In addition to the compound of formula (1), preferably of formula (1-a),the corresponding aziridine according to formula (19), preferably offormula (19-a), or salt thereof, may form when R1, for the compound offormula (11), preferably of formula (11-a) is hydrogen.

The compound according to formula (19), which is described in J. Org.Chem., 1988, 53, 4006, or salt thereof, may be isolated, allowing theconversion of the compound of formula (11) to the compound of formula(1) to proceed in a step-wise manner. Alternatively, the compound offormula (19) may be generated in situ.

Subsection C-4: Method 4

An alternative preparation method of the Key Lactam (1), or saltthereof, is oxidation of the primary alcohol of pyroglutaminol to thealdehyde followed by the addition of activated (e.g. metallated)biphenyl and the removal of the secondary alcohol (e.g. by hydrogenationor reduction). The addition of activated (e.g. metallated) biphenyl toan aldehyde of formula (12), or salt thereof, may be achieved by methodswell known in the art, for example, as described in J. Org. Chem., 1987,52, 4352. Moreover, methods to prepare compounds of the formula (12), orsalts thereof, are described in the literature, for example, inBiochemistry, 1985, 24, 3907.

Hence, a further subject of the present invention is a process forpreparing a compound according to formula (1), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, as defined above,comprising the following steps:

-   a) providing a compound according to formula (12), or salt thereof,

-   -   wherein R1 is hydrogen or a nitrogen protecting group, as        defined above,

-   b) reacting compound (12), or salt thereof, with an activated (e.g.    metallated) biphenylic compound to obtain a compound according to    formula (13), or salt thereof,

-   -   wherein R1 is hydrogen or a nitrogen protecting group, as        defined above, and

-   c) reducing the compound according to formula (13), or salt thereof,    to obtain the compound according formula (1), or salt thereof.

In another embodiment, the present invention relates to the aboveprocess comprising the steps (a) to (c) and it also relates to each ofreaction steps (a) to (c). In still another embodiment, the presentinvention also relates to the product obtained according to each of thereaction steps (a) to (c) and to the product obtained according to thecomplete reaction sequence (a) to (c).

R1 can be a nitrogen protecting group as described above in section A:The Key Lactam (1), or salt thereof, as such. Preferably, R1 ishydrogen.

Regarding the term “activated biphenylic compound” it is referred to theexplanations above for method 1 in section C-1. Preferably the activatedbiphenylic compound is a metallated biphenyl, eg. biphenylmagnesiumhalide, especially biphenylmagnesium bromide.

The secondary alcohol according to formula (13), or salt thereof,generally can be reduced according to known methods. In a preferredembodiment the OH group is converted into a leaving group. Preferredleaving groups are described above in subsection C-4. Subsequenttreatment with a reducing agent would lead to a compound according toformula (1), or salt thereof. Suitable reducing agents are described,for example, above in subsection C-1.

In a preferred embodiment the compounds (12) and (13), or salts thereof,have a configuration according to formulae (12-a) and (13-a)

wherein R1 is defined as above for compounds (12) and (13). Furthermore,preferably a compound according to formula (1-a), or salt thereof, isobtained.

The preparation of compounds of formula (12) is described in theliterature, for example in Biochemistry, 1985, 24, 3907.

In a preferred embodiment, the reaction of a compound of formula (12) toprovide a compound of formula (13) is analogous to the Grignard additiondescribed in JOC 1987, 52, 4352.

Subsection C-5: Method 5

An alternative preparation method of the Key Lactam (1) is a reactionstarting from 1,5-dihydropyrrol-2-one, or salt thereof, employing achemo- and enantio-selective hydrogenation as the key step.

Hence, a further subject of the present invention is a process forpreparing a compound according to formula (1), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, as defined above,comprising the following steps:

-   a) providing a compound according to formula (14), or salt thereof,

-   b) reacting the compound according to formula (14), or salt thereof,    with 4-formyl biphenyl to obtain a compound according to formula    (15), or salt thereof,

-   c) hydrogenating compound (15), or salt thereof, to obtain a    compound according to formula (16), or salt thereof,

and

-   d) reducing the compound according to formula (16), or salt thereof,    to obtain a compound according to formula (1), or salt thereof,    wherein in formulae (14) to (16) R1 is hydrogen or a nitrogen    protecting group, as defined above.

In another embodiment, the present invention relates to the aboveprocess comprising the steps (a) to (d) and it also relates to each ofthe reaction steps (a) to (d). In still another embodiment, the presentinvention also relates to the product obtained according to each of thereaction steps (a) to (d) and to the product obtained according to thecomplete reaction sequence.

R1 can be a nitrogen protecting group as described above in section A:The Key Lactam (1), or salt thereof, as such. Preferably, R1 ishydrogen.

The reaction of the compound according to formula (14), or salt thereof,with 4-formyl biphenyl preferably is carried out in the presence of abase, particularly sodium hydroxide.

The hydrogenation of compound (15), or salt thereof, to obtain compound(16), or salt thereof, is preferably carried out by an enantioselectivehydrogenation, preferably as described below.

The hydrogenation of compound (16), or salt thereof, to obtain compound(1), or salt thereof, is preferably carried out with palladium on carbonas catalyst.

Alternatively, a compound of formula (16), or salt thereof, can beconverted into a compound of formula (1), or salt thereof, underreduction conditions, for example, by the use a hydride reducing agent,such as NaBH₄—NiCl₂, NaBH₄—BiCl₃, or NaBH₄—InCl₃.

In a preferred embodiment the configuration of compound (16), or saltthereof, is according to formula (16-a)

wherein R1 is as defined above in formula (16). Furthermore, preferablya compound according to formula (1-a), or salt thereof, is obtained.

A preferred embodiment of method 5 is exemplified in Scheme 8 below.

In another embodiment, the present invention relates to the completereaction sequences described in Scheme 8 converting the compound offormula (14), as defined herein, into the compound of formula (1-a), asdefine herein, and it also relates to each of the reaction steps shownin Scheme 8. In still another embodiment, the present invention relatesto the product obtained according to the complete reaction sequencedescribed in Scheme 8, and it also relates to the product obtainedaccording to each of the reaction steps shown in Scheme 8.

The compound of formula (14), or salt thereof, wherein R1 is hydrogen iscommercially available, for example from suppliers such as J & WPharmaLab LLC. Treatment of a compound of formula (14), wherein R1 is H,with a suitable nitrogen protecting agent, as defined above, to protectthe N with a protecting group PG can be accomplished, according to themethods described above.

Conversion of a compound of formula (14), or salt thereof, wherein R1 ishydrogen or a nitrogen protecting group, into a compound of formula(15), or salt thereof, wherein R1 is hydrogen or a nitrogen protectinggroup, can be achieved upon reaction with biphenyl-4-carbaldehyde in thepresence of a base, such as an alkalimetal base (e.g. NaOH or KOH), forexample, as described in J. Org. Chem., 2002, 67 (14), 4702, inSynthesis, 2004, (10), 1560 and in Synth. Commun., 2002, 32 (7), 1031.

Chemoselective and enantioselective hydrogenation of a compound offormula (15), or salt thereof, wherein R1 is hydrogen or a nitrogenprotecting group, into a compound of formula (16-a), or salt thereof,wherein R1 is hydrogen or a nitrogen protecting group, can be achieved,by the use of, for example, asymmetric hydrogenation conditions employedfor enamide substrates, such as conditions described in TetrahedronAsymm., 1991, 2(1), 51, in particular for compounds of formula 8a and 8btherein, or as described in J Org Chem 1994, 59(2), 297.

Reduction of the compound of formula (16-a), or salt thereof, wherein R1is hydrogen or a nitrogen protecting group, into the compound of formula(1-a), or salt thereof, wherein R1 is hydrogen or a nitrogen protectinggroup, can be effected, for example, under hydrogenation conditions, forexample, by the use of Pd/C as described, for example, in Synthesis,1993, 216, or by the use of a reducing agent, for example by the use ofa hydride reagent, such as NaBH₄, as described, for example, in J. Org.Chem, 2006, 71(5), 2173, in particular, as described in the conversionof the compound 8 into the compound 15, therein.

A preferred embodiment of the method described in Scheme 8 relates tocompounds wherein R1 is hydrogen. A further preferred embodiment of themethod described in Scheme 8 relates to compounds wherein R1 is hydrogenand wherein the reduction of the compound (16-a) to (1-a) takes placewith Pd/C and hydrogen.

Alternatively, a compound of formula (14), or salt thereof, can beconverted into a compound of formula (1), preferably of formula (1-a),or salts thereof, as detailed in Schemes 9 to 12 below. In a preferredembodiment of the methods described in Schemes 9 to 12, R1 for compoundstherein is hydrogen.

In another embodiment, the present invention relates to the completereaction sequences described in Scheme 9 converting the compound offormula (14), as defined herein, into the compound of formula (1-a), asdefine herein, and it also relates to each of the reaction steps shownin Scheme 9. In still another embodiment, the present invention relatesto the product obtained according to the complete reaction sequencedescribed in Scheme 9, and it also relates to the product obtainedaccording to each of the reaction steps shown in Scheme 9.

Scheme 9 encompasses a particular embodiment of Scheme 8, wherein theenantioselective hydrogenation of the compound of formula (15), as abovedetailed, leads directly to the compound of formula (1-a). Namely, thisembodiment refers to the enantioselective hydrogenation of the compoundof formula (15), or salt thereof, wherein there is no chemoselectivityand thus both the endo and exo C═C bonds of the pyrrolidinone moiety arereduced under the enantioselective hydrogenation conditions.

In another embodiment, the present invention relates to the completereaction sequences described in Scheme 10 converting the compound offormula (14), as defined herein, into the compound of formula (1-a), asdefine herein, and it also relates to each of the reaction steps shownin Scheme 10. In still another embodiment, the present invention relatesto the product obtained according to the complete reaction sequencedescribed in Scheme 10, and it also relates to the product obtainedaccording to each of the reaction steps shown in Scheme 10.

Scheme 10 describes an alternative route, wherein the reduction of acompound of formula 15, or salt thereof, wherein R1 is hydrogen or anitrogen protecting group, is chemoselective and provides the compoundof formula (16), or salt thereof, wherein R1 is hydrogen or a nitrogenprotecting group. This chemoselective hydrogenation can be accomplished,for example, under conditions which employ Na₂(S₂O₄) and NaHCO₃ in DMF,as described in Monatshefte fuer Chemie 1995, 126(3), 355, inMonatshefte fuer Chemie 1986, 117(2), 185 and in Liebigs Annalen derChemie, 1986, 1241. Alternatively, it can be achieved by the use ofPd/C, for example, as described in Helv. Chim. Acta, 1987, 70(8), 2098.Racemic resolution of the compound of formula (16), or salt thereof, forexample, as described for compound of formula 5 in Helv Chim Acta 1987,70, 2098 and subsequent reduction of the resulting compound of formula(16-a), for example, under the same reactions conditions described inScheme 8, can lead to the compound of formula (1-a), or salt thereof.These two last steps, racemic resolution and reduction can be performedin reverse order, namely, reduction of the compound of formula (16), orsalt thereof, for example under the same reactions conditions describedabove for the compound of formula (16-a) in Scheme 8, followed byracemic resolution of the compound of formula (1), or salt thereof, forexample, under the same reactions conditions described above for thecompound of formula (16).

In another embodiment, the present invention relates to the completereaction sequences described in Scheme 11 converting the compound offormula (14), as defined herein, into the compound of formula (1-a), asdefine herein, and it also relates to each of the reaction steps shownin Scheme 11. In still another embodiment, the present invention relatesto the product obtained according to the complete reaction sequencedescribed in Scheme 11, and it also relates to the product obtainedaccording to each of the reaction steps shown in Scheme 11.

Another alternative route to convert the compound of formula (14), orsalt thereof, into the compound of formula (1-a), or salt thereof, isdetailed in Scheme 11. According to this route the reduction of thecompound of formula (15), as defined above, or salt thereof leadsdirectly to the compound of formula (1), as defined herein, or saltthereof. This reduction can be achieved, for example, under standardhydrogenation conditions, such as Pd/C and hydrogen. Subsequently,racemic resolution, as described above, can lead to the compound offormula (1-a), as defined herein, or salt thereof.

In another embodiment, the present invention relates to the completereaction sequences described in Scheme 12 converting the compound offormula (14), as defined herein, into the compound of formula (1-a), asdefine herein, and it also relates to each of the reaction steps shownin Scheme 12. In still another embodiment, the present invention relatesto the product obtained according to the complete reaction sequencedescribed in Scheme 12, and it also relates to the product obtainedaccording to each of the reaction steps shown in Scheme 12.

According to Scheme 12, the compound of formula (15), as defined herein,or salt thereof, alternatively, can be reduced chemoselectively to thecompound of formula (21), or salt thereof, wherein R1 is hydrogen or anitrogen protecting group. This reduction can be effected, for example,as described for the compound of formula (16-a) in Scheme 8.Subsequently, the compound of formula (21), as described herein, or saltthereof, can be converted into the compound of formula (1-a), or saltthereof, under enantioselective hydrogenation reaction conditions, forexample, as described in J. Chem. Soc., Perkin Trans 1, 1998, 1403, inparticular as described for compounds 7a-d therein. Alternatively,standard hydrogenation, for example by the use of Pd/C and hydrogen, ofsaid compound of formula (21), or salt thereof, can afford the compoundof formula (1) or salt thereof. Racemic resolution, as described above,can lead to the compound of formula (1-a), as defined herein, or saltthereof.

Subsection C-6: Method 6

Method 6 for preparing the Key Lactam (1), or salt thereof, alsocomprises the reaction step of reducing a compound according to formula(16), or salt thereof. However, the method for preparing compound (16),or salt thereof, differs from method 5.

Method 6 comprises a synthesis from 1,5-dihydropyrrol-2-one, or saltthereof, optionally using a chiral phase transfer catalyst to establishthe desired configuration at the chiral centre of the compound offormula (16). Subsequent reduction, for example by hydrogenation, forexample, as described above for a compound of formula (16-a) in Scheme8, yields the Key Lactam (1), or salt thereof.

Hence, a further subject of the present invention is a process forpreparing a compound according to formula (16), or salt thereof,

comprising reacting a compound according to formula (14), or saltthereof,

with an activated 4-methyl biphenyl to obtain a compound according toformula (16), or salt thereof, in the presence of a base, preferably inthe presence of a base and a chiral phase transfer catalyst, wherein informulae (14) and (16) R1 is hydrogen or a nitrogen protecting group, asdefined above.

R1 can be a nitrogen protecting group as described above in section A:The Key Lactam (1), or salt thereof, as such. Preferably, R1 ishydrogen.

Preferably, a chiral phase transfer catalyst is used to produce compound(16), or salt thereof, having a configuration as shown in formula(16-a). Preferably the Key Lactam, or salt thereof, having aconfiguration according to formula (1-a) is produced.

Generally, known phase transfer catalysts are suitable. Examples ofchiral phase transfer catalysts include chiral crown ethers or, morepreferably, cinchona alkaloids. Specific examples of suitable chiralphase transfer catalysts are given in issue 17, pages 1 to 15 of“Industrial Phase-Transfer Catalysis”, published by PTC Communications,Inc., 900 Briggs Road, Suite 145, Mt. Laurel, N.J. 08054 USA.

The activated 4-methyl biphenyl is a compound of the formulaPh-Ph-CH₂—X, wherein X is a leaving group. Generally, the explanationsgiven above in subsection C-3 for leaving groups apply. Preferably, X ishalogen, especially bromide.

In a preferred embodiment, the base used in this step is an alkyllithiumbase, such as BuLi, or an alkali metal hydroxide, such as KOH, or isLDA; for example, as described in Synlett, 2003, (2), 271, in Synlett,2004, (2), 247 and in Perkin Transactions 1, 1990, (8), 2350.

In a particular embodiment of this route, compounds of formula (16) or(1), or salts thereof, can be resolved, as detailed in subsection C-5,to provide compounds of formula (16-a) or (1-a), or salts thereof,respectively.

A preferred embodiment of method 6 is exemplified in Scheme 13 below.

In another embodiment, the present invention relates to the completereaction sequences described in Scheme 13 converting the compound offormula (14), as defined herein, into the compound of formula (1-a), asdefine herein, and it also relates to each of the reaction steps shownin Scheme 13. In still another embodiment, the present invention relatesto the product obtained according to the complete reaction sequencedescribed in Scheme 13, and it also relates to the product obtainedaccording to each of the reaction steps shown in Scheme 13.

A preferred embodiment of the method described in Scheme 13 relates tocompounds wherein R1 is hydrogen. A further preferred embodiment of themethod described in Scheme 13 relates to compounds wherein R1 ishydrogen and wherein the reduction of the compound (16-a) to (1-a) takesplace with Pd/C and hydrogen.

Particularly preferred bases and chiral transfer catalysts of the firststep (conversion of a compound of formula (14), or salt thereof, into acompound of formula (16-a), or salt thereof) in this embodiment areselected, for example, from the group of bases and chiral catalystsabove mentioned. Subsequent reduction of the compound of formula (16-a),or salt thereof, to yield the compound of formula (1-a), or saltthereof, can be accomplished, for example, under hydrogenationconditions by the use of Pd/C or as described in previous subsectionC-5.

Subsection C-7: Method 7

Method 7 for preparing the Key Lactam (1), or salt thereof, alsocomprises the reaction steps of hydrogenating a compound according toformula (15), or salt thereof, to obtain compound (16), or salt thereof,and reducing a compound according to formula (16), or salt thereof, toobtain the Key Lactam (1), or salt thereof. However, the method forpreparing compound (15), or salt thereof, differs from method 5.

Method 7 starts from an N-protected succinimide, or salt thereof,followed by a chemo- and enantio-selective hydrogenation as the keystep.

Hence, a further subject of the present invention is a process forpreparing a compound according to formula (15), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, as defined above,comprising reacting a compound according to formula (17), or saltthereof,

with an organometallic reagent derived from 4-methyl biphenyl to obtaina compound according to formula (15), or salt thereof. In a preferredembodiment according to this process, the compound of formula (15) hasthe following stereochemistry

wherein R1 is hydrogen or a nitrogen protecting group, as defined above.

Preferably R1 is hydrogen or a nitrogen protecting group as describedabove in section A: The Key Lactam (1), or salt thereof, as such. Inparticular, R1 is pivaloyl or BOC.

The organometallic reagent derived from 4-methyl biphenyl preferably isa compound of the formula Ph-Ph-CH₂—Y, preferably 4-biphenyl-CH₂—Y,wherein Y is a nucleophilic group. Preferred compounds of formulaPh-Ph-CH₂—Y, preferably 4-biphenyl-CH₂—Y, are, for example,4-biphenylmethylmagnesium halides (Grignard reagents). The nucleophilicgroup Y is preferably a group MX, wherein X is a halogen and M is Mg orZn. Suitable halides generally are chloride, bromide and iodide, whereinbromide is especially preferred.

Further examples for organometallic reagents derived from 4-methylbiphenyl are 4-biphenylmethyllithium, 4-biphenylmethylcuprate (low- andhigher-order cuprates), 4-biphenylmethylzinc. These compounds can beused individually or in the presence of another metal, e.g. copper,zinc, palladium, platinum, iron, iridium or ruthenium.

Preferably, in the above formula Y is MgBr (4-biphenylmethylmagnesiumbromide).

A preferred embodiment of method 7 is exemplified in Scheme 14 below.

In another embodiment, the present invention relates to the completereaction sequences described in Scheme 14 converting the compound offormula (17), as defined herein, into the compound of formula (1-a), asdefine herein, and it also relates to each of the reaction steps shownin Scheme 14. In still another embodiment, the present invention relatesto the product obtained according to the complete reaction sequencedescribed in Scheme 14, and it also relates to the product obtainedaccording to each of the reaction steps shown in Scheme 14.

In this embodiment, a compound of formula (15), or salt thereof, isprepared from a compound of formula (17), or salt thereof, underGrignard conditions, for example, analogous to those described in PerkinTransactions 1, 1993, (21), 2567. Next, the compound of formula (15), orsalt thereof, can be converted into the compound of formula (16-a), orsalt thereof, via enantioselective hydrogenation, for example, asdescribed above. Further reduction of the compound of formula (16-a), orsalt thereof, to yield the compound of formula (1-a), or salt thereof,can be accomplished, for example, under hydrogenation conditions. In apreferred embodiment, the reduction of the compound of formula (16-a),or salt thereof, is achieved by the use of Pd/C. Alternatively, thecompound of formula (15), which is prepared from a compound of formula(17) as described above, can be converted into the compound of formula(1), preferably of formula (1-a), as described in Schemes 9 to 12.

Subsection C-8: Method 8

In still another embodiment of the present invention, the compound offormula (21), or salt thereof, wherein R1 is hydrogen or a nitrogenprotecting group, as described above, can be prepared from a compound offormula (6), or salt thereof, wherein R1 is hydrogen or a nitrogenprotecting group, for example, as described in Scheme 14.

In another embodiment, the present invention relates to the completereaction sequences described in Scheme 14 converting the compound offormula (6), as defined herein, into the compound of formula (21), asdefine herein, and it also relates to each of the reaction steps shownin Scheme 14. In still another embodiment, the present invention relatesto the product obtained according to the complete reaction sequencedescribed in Scheme 14, and it also relates to the product obtainedaccording to each of the reaction steps shown in Scheme 14.

In this embodiment, a compound of formula (22), or salt thereof, whereinR1 is hydrogen or a nitrogen protecting group, is prepared from acompound of formula (6), or salt thereof, wherein R1 is hydrogen or anitrogen protecting group, for example, by the use of an organometallicreagent derived from 4-methyl biphenyl, as described above. Next, thecompound of formula (22), or salt thereof, is converted into thecompound of formula (21), wherein R1 is as above described, or saltthereof, under dehydration conditions, for example by the use of theBurgess reagent. Alternatively, the tertiary alcohol maybe activated,for example by being mesylated, and subsequent treatment with a base,for example, NaOH, may provide the compound of formula (21) or saltthereof.

In a preferred embodiment according to the process outlined in Scheme14, the compound of formula (21) has the following stereochemistry

wherein R1 is hydrogen or a nitrogen protecting group, as defined above.

The compound of formula (21), or salt thereof, preferably of formula(21-a), can be converted into the compound of formula (1), or saltthereof, preferably of formula (1-a), or salt thereof, for example, asabove described.

Section D: Novel And Inventive Compounds Occurring In One Of ThePrecedent Sections

In the processes shown above several novel and inventive compounds areinvolved. Consequently, further subjects of the present invention arethe compounds shown below.

A compound according to formula (2), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, as defined above,preferably having a configuration according to formula (2-a)

In a preferred embodiment of formula (2-a) R1 is hydrogen or a nitrogenprotecting group selected from pivaloyl and t-butyloxycarbonyl (BOC).

A compound according to formula (4), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, as defined above,and R4 is morpholine, preferably having a configuration according toformula (4-a)

wherein R1 and R4 are defined as above in formula (4).

A compound according to formula (8), or salt thereof,

wherein R1 and R2 are independently, of each other, hydrogen or anitrogen protecting group, as defined above, and R5 is hydrogen oralkyl, preferably having a configuration according to formula (8-a)

A compound according to formula (9), or salt thereof,

wherein R1 and R2 are independently, of each other, hydrogen or anitrogen protecting group, as defined above, and R5 is hydrogen oralkyl, preferably having a configuration according to formula (9-a)

A compound according to formula (10), or salt thereof,

wherein R5 is hydrogen or alkyl, preferably having a configurationaccording to formula (10-a)

A compound according to formula (13), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, as defined above,preferably having a configuration according to formula (13-a)

A compound according to formula (15), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, as defined above.

A compound according to formula (16), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, as defined above,preferably having a configuration according to formula (16-a)

A compound according to formula (20), or salt thereof,

preferably having a configuration according to formula (20-a)

wherein in the above formulae R1 is hydrogen or a nitrogen protectinggroup, as defined above, R10 is a group which can be saponified and/ordecarboxylated, as defined herein, and R11 is hydrogen or methyl.Preferably, R10 is —O-alkyl, in particular —O-Et or —O-Me, preferably—O-Et, or is —O-aryl, in particular aryl is phenyl. In another preferredembodiment R10 is —O-alkylaryl, for example, —O-benzyl.

A compound according to formula (21), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, as defined above.

A compound according to formula (22), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, as defined above.

A compound according to formula (5), or salt thereof, in crystallineform,

wherein R1 is hydrogen or a nitrogen protecting group, as defined above,preferably having a configuration according to formula (5-a)

In a preferred embodiment the crystalline compounds according to formula(5-a), or salts thereof, comprise a monoclinic crystal system. Furtherpreferred, the crystalline products of the invention comprise the spacegroup P21.

In further embodiment, the invention relates to a compound of theformula (1), (1-a), (1-b), (1′), (1″), (1′-a), (1″-a), (2), (2-a),(2-b), (2′), (2′-a), (2″), (2″-a), (3), (3-a), (3-b), (4), (4-a), (5),(5-a), (7), (7-a), (8), (8-a), (9), (9-a), (10), (10-a), (11), (11-a),(12), (12-a), (13), (13-a), (14), (15), (15-a), (16), (16-a), (17),(18), (19), (20), (20-a), (21), (21-a) or (22), or salts thereof, asdefined hereinbefore or hereinafter; more preferably a compound of theformula (1), (1-a), (1-b), (1′), (1″), (1′-a), (2), (2-a), (2-b), (2′),(2′ a), (3), (3-a), (4), (4-a), (5), (5-a), (7), (7-a), (8), (8-a), (9),(9-a), (10), (10-a), (13), (13-a), (15), (16), (16-a), (20), (20-a),(21) or (22), or salts thereof, as defined hereinbefore or hereinafter;in particular wherein R1 is selected from the preferred definitionsdescribed hereinbefore.

In still further embodiment, the invention relates to a compound of theformula (1), (2), (3) or (10), preferably (1-a), (2-a) or (10-a), orsalts thereof, in crystalline form, as defined hereinbefore orhereinafter.

Particular embodiments of the invention are provided in the Examples—theinvention thus, in a very preferred embodiment, relates to a compound ofthe formula above mentioned or a salt thereof, selected from thecompounds given in the Examples, as well as the use thereof according tothe invention.

Section E: Examples

The following Examples serve to illustrate the invention withoutlimiting the scope thereof, while they on the other hand representpreferred embodiments of the reaction steps, intermediates and/or theprocess of the present invention.

Abbreviations

-   δ chemical shift-   μl microlitre-   Ac acetyl-   Bn benzyl-   Boc tert-butoxycarbonyl-   BOC₂O di-tert-butyl carbonate-   Cbz benzyl carbamate-   Cbz-Cl benzyl chloroformate-   de diastereomeric excess-   DMAP 4-(dimethylamino)pyridine-   DMF N,N-dimethylformamide-   DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone-   DMSO dimethylsulfoxide-   ee enantiomeric excess-   ES electrospray-   ESI electrospray ionisation-   Et ethyl-   EtOAc ethyl acetate-   h hour(s)-   HNMR proton nuclear magnetic resonance-   HOBt 1-hydroxybenzotriazole-   HPLC high performance liquid chromatography-   i-Pr isopropyl-   iPrOAc isopropyl acetate-   IR infra red-   KHMDS potassium bis(trimethylsilyl)amide-   L litre-   LC-MS liquid chromatography-mass spectrometry-   LDA lithium diisopropylamide-   LHMDS lithium bis(trimethylsilyl)amide-   M molarity-   m/e mass-to-charge ratio-   Me methyl-   mg milligram-   min minute(s)-   mL millilitre-   mmol(s) millimole(s)-   mol(s) mole(s)-   MS mass spectrometry-   NaHMDS sodium bis(trimethylsilyl)amide-   nm nanometre-   NMR nuclear magnetic resonance-   Pd/C palladium on carbon-   Ph phenyl-   Piv pivaloyl-   Piv-Cl pivaloyl chloride-   ppm parts per million-   psi pounds per square inch-   RT room temperature-   SEM 2-(Trimethylsilyl)ethoxymethyl-   SEM-Cl (2-chloromethoxyethyl)-trimethylsilane-   TES triethylsilyl-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TLC thin layer chromatography-   TMEDA N,N,N,N-tetramethylethylenediamine-   t_(R) retention time-   Ts tosylate/tosyl

In quoting NMR data, the following abbreviations are used: s, singlet;d, doublet; t, triplet; q, quartet; quint., quintet; m, multiplet.

Example 1-1 (S)-5-(morpholine-4-carbonyl)pyrrolidin-2-one

Method 1

To a mixture of 48 g dicyclohexylcarbodiimide, 30 g commerciallyavailable L-pyroglutamic acid and 3.1 g hydroxybenzotriazole 20.2 g ofmorpholine were added in 170 ml dichloromethane at about −15° C. Themixture was allowed to warm to room temperature. The suspension wasfiltered and diluted with 290 ml THF. The mixture was concentrated toobtain a suspension, which was filtered yielding 41 g of(S)-5-(morpholine-4-carbonyl)pyrrolidin-2-one.

Melting point (hereinafter referred to as “mpt”): 130-132° C. ¹H-NMR(DMSO): 1.87 (1H); 2.19 (1H); 2.28 (1H); 3.35-3.65 (8H); 4.51 (1H); 7.70(1H). MS (ESI, m/e) 199 [M+H]⁺; 397 [2M+H]⁺.

Enantiomeric excess (ee): 98.0% (4-a, R1=H; R4=morpholine) as determinedby GC.

Method 2

A suspension of 5 g S-pyroglutamic acid (38.737 mmol) in 50 ml THF and250 l DMF is cooled to 0° C. and 3.09 ml (5.07 g, 42.611 mmol)thionylchloride is added within 5 min. The reaction mixture is allowedto warm up to room temperature within 2 h. The resulting clear solutionis again cooled to 0° C. and is then treated with 7.25 ml (7.25 g, 170.1mmol) morpholine. After warming up the reaction mixture to ambienttemperature within 2 h, the suspension is filtered.

The filtrate is concentrated under reduced pressure to give a cruderesidue. Enantiomeric excess (ee): 98.0% (4-a, R1=H; R4=morpholine) asdetermined by GC

Method 3

The reaction vessel is charged with 30 g L-pyroglutamic acid and 4.71 g1-hydroxybenzotriazole hydrate. The solids are then suspended in 190 mlanhydrous acetonitrile and the mixture is then heated to 45° C.Subsequently, 20.24 ml morpholine is added via a dropping funnel within20 min, and the dropping funnel is then washed with 5 ml anhydrousacetonitrile. The resulting mixture is then heated to 65° C. and 29.32 gN—N′-diisopropylcarbodiimide added within 1 h via a dropping funnel.After complete addition, the dropping funnel is washed with 5 mlanhydrous acetonitrile and the reaction mixture is stirred at 65° C. foran additional 30 min. The resulting suspension is then cooled to ambienttemperature, filtered and the filter cake washed with 3×30 mlacetonitrile. The filtrate is concentrated under heating and reducedpressure to approx. ½ of its original volume and the residue is thenseeded with 16 mg (S)-5-(morpholine-4-carbonyl)pyrrolidine-2-one.Concentration under reduced pressure is continued until approx ⅓ of theoriginal volume of the filtrate is reached. While further concentratingthe filtrate under reduced pressure and removing approx. 95 ml ofdistillate, simultaneously 210 ml 2-methyltetrahydrofuran is added. Thesuspension is then cooled to 0° C. and the solids are isolated byfiltration. The filter cake is washed with 3×20 ml icooled2-methyltetrahydrofuran and dried at 55° C. under vacuum to give 42.54 gof (S)-5-(morpholine-4-carbonyl)pyrrolidine-2-one as fine white crystals(98.0% purity by HPLC, ee (HPLC)>99.6% [4-a, R1=H; R4=morpholine]).

Example 1-2 (R)-5-(morpholine-4-carbonyl)pyrrolidin-2-one

To a mixture of 30 g R-pyroglutamic acid and 4.71 g hydroxybenzotriazolein 200 ml acetonitrile is added 20.24 g of morpholine at 50° C. Themixture is heated to 60° C. and 29.32 g N,N′-diisopropylcarbodiimide areadded. After 1 h, the suspension is cooled to room temperature and theprecipitate removed by filtration. The mother liquor is distilled underreduced pressure. During the distillation methyltetrahydrofuran isadded. The resulting suspension is cooled to 0° C. and then filtered.The filter cake is washed with methyltetrahydrofuran and dried underreduced pressure to yield (R)-5-(morpholine-4-carbonyl)pyrrolidin-2-one.¹H-NMR (DMSO): 1.88 (1H); 2.11 (1H); 2.32 (1H); 3.46 (4H); 3.59 (4H);4.54 (1H, dd, J=3.3, 8.8); 7.72 (1H). MS (ESI, m/e) 199 [M+H]⁺; 397[2M+H]⁺. IR (solution in CH₂Cl₂, /cm⁻¹): 3341; 2860; 1709; 1694; 1639;1462; 1270; 1255; 1116; 655. Enantiomeric excess (ee): 99.6% (4-b, R1=H;R4=morpholine) as determined by GC

Example 1-3 (R/S)-5-(morpholine-4-carbonyl)pyrrolidin-2-one

A mixture of 143 g of pyroglutamic acid methyl ester (1 mol) and 139 gmorpholine (1.60 mol) in 900 ml of xylene is heated to 140° C. for 20 h.The xylene is evaporated to a volume of 500 ml. From the suspensionobtained, the precipitate is filtered off, washed with THF to yield thedesired compound after drying in vacuo. From the filtrate the solvent isevaporated completely. This crude product[(R/S)-5-(morpholine-4-carbonyl)pyrrolidin-2-one] is filtered over 800 gsilica gel with THF as the solvent and evaporated to dryness to yield asecond crop of the desired compound. This compound is used directly inthe next step. HPLC analysis shows the material to be in an enantiomericratio: 55.8:44.2 [(4-a, R1=H; R4=morpholine): (4-b, R1=H;R4=morpholine), respectively].

Example 1-4 (S)-5-(morpholine-4-carbonyl)pyrrolidin-2-one

L-pyroglutamic acid methyl ester (23.91 g, 177 mmol), morpholine (21.8g, 250 mmol) and 4-dimethylaminopyridine (0.2 g, 1.64 mmol) are heatedunder reflux in toluene (130 ml) for 12 hours. The product precipitatesas an oil. The oil is separated from the toluene, diluted withdichloromethane (100 ml) and washed successively with 0.1 M HCl, 0.1 MNaOH and water (50 ml each). The dichloromethane phase is concentratedto obtain a suspension, which is filtered yielding the crude product.The crude product is dissolved in THF (200 ml) at 45° C. and, uponcooling in an ice bath, (S)-5-morpholine-4-carbonyl)pyrrolidin-2-oneprecipitates as white crystals. Enantiopurity (GC) 88.7% (S)-Enantiomer.

Example 1-5 (R/S)-5-(morpholine-4-carbonyl)pyrrolidin-2-one

A mixture of 14.5 g of pyroglutamic acid methylester (100 mmol) and 13.1g morpholine (150 mmol) in 80 ml of toluene is heated to reflux (110°C.) for 48 h. During this reaction time, methanol formed is distilledfrom the reaction mixture. Finally two phases are formed. The upper,toluene phase, was decanted and the lower product phase is filtered oversilica gel (180 g) with ethyl acetate:methanol=70:30. the solvent isevaporated to yield the product as an oil. The enantiomeric ratio is93:7 [(4-a, R1=H; R4=morpholine) to (4-b, R1=H; R4=morpholine),respectively] and the GC purity is 96.4% area %.

HPLC Method (Example 1):

Column: Chirobiotic-T; 100×4.6 mm; 5 μm. Mobile Phase A (0.01 M NH₄OAcin MeOH+0.1% TFA). Isocratic: 0 min (100%); 10 min (100% A). Flow rate:1.0 ml min⁻¹. Wavelength: 210 nm. Column temperature: 10° C.

Retention Times:

4-a (R1=H; R4=morpholine): 2.3 min

4-b (R1=H; R4=morpholine): 2.8 min

GC Method (Example 1):

Column: Fused-Silica-Capillary, CHIRALDEX G-BP; 20 m×0.25 mm.Pre-column: Deactivated fused silica, 1 m×0.53 mm. Injection blocktemperature: 250° C. Detector temperature: 300° C. Carrier gas: helium,3.0 ml min⁻¹, constant flow. Injection volume: 2.0 μl. Split ratio:20:1. Oven temperature: 200° C. (initial) isocratic for 50 min.

Retention Times:

4-a (R1=H; R4=morpholine): 27.5 min

4-b (R1=H; R4=morpholine): 30.1 min

Example 2-1 (S)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one

Method 1

39 g of (S)-5-(morpholine-4-carbonyl)pyrrolidin-2-one of example 1 weresuspended in 300 ml of dry, degassed THF. The solution was cooled toabout −15° C. 200 ml of a 2.2 M solution of 4-biphenylmagnesiumbromidein THF were added over about 20 min. The mixture was allowed to warm toroom temperature over about 19 hours. The mixture was quenched by theaddition of ice-cold 2 M hydrochloric acid and the organic layer wasseparated. A partial concentration yielded a precipitate, which wascollected by filtration, washed with water and toluene to obtain 44 g of(S)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one. mpt 163-203° C. (decomp.).¹H-NMR (DMSO): 1.88 (1H); 2.15 (2H); 2.53 (1H); 5.30 (1H); 7.34-7.60(3H); 7.77 (2H); 7.90 (3H); 8.11 (2H). Enantiomeric excess (ee): 98.08%(5-a, R1=H) as determined by hplc.

The X-ray Structure of the obtained crystals is shown in FIG. 4.Respective crystal data is as follows:

Empirical formula C₁₇H₁₅NO₂; formula weight 265.30; temperature 100(2)K; wavelength 1.54178 Å; crystal system monoclinic; space group P21 unitcell dimensions a=10.362(3) Å, a=90°, b=8.236(2) Å, b=90.872(15)°,c=15.583(4) Å, g=90°; volume 1329.7(6) Å3; Z 4; density (calculated)1.325 mg/m³; absorption coefficient 0.698 mm⁻¹; F(000) 560.

Reflections in the X-ray diffraction pattern show the followinginterlattice plane intervals (average 2θ in [°] are indicated with errorlimit of ±0.2): 2θ in [°]: 3.8, 5.6, 8.3, 10.1, 13.4, 14.2, 14.6, 17.6,18.9, 19.8, 20.4, 20.7, 21.1, 22.7. Data taken using a Bruker D8 Advancediffractometer using Cu-Kα radiation.

Method 2

50 g of (S)-5-(morpholine-4-carbonyl)pyrrolidin-2-one are suspended in450 ml of THF. The solution is then cooled to about −5° C. Next, 127 mlof isopropylmagnesium chloride solution in THF (1.90 M) is added over 30min. The mixture is stirred for a further 30 min and then 300 ml of4-biphenylmagnesium bromide solution in THF (1.01 M) is added. Themixture is warmed to room temperature. Stirring is continued for 10 h.The mixture is then added to 585 ml hydrochloric acid (2 M) at 0° C. Themixture is then warmed to room temperature. Subsequently, 162 ml sodiumhydroxide (2 M) is added. The mixture is heated to 60° C. and thevolatile solvents removed under vacuum. To the residue is added 250 mltoluene and the mixture is stirred for 30 min. The mixture is cooled toroom temperature. A solid is collected by filtration and washed with 150ml toluene and 150 ml water to provide, after drying,(S)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one. Enantiomeric excess (ee):99.8% (5-a, R1=H) as determined by hplc.

Example 2-2 (R)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one

35.48 g of (R)-5-(morpholine-4-carbonyl)pyrrolidin-2-one are suspendedin 302 ml of dry, degassed THF. The solution is cooled to −5° C. 92.3 mlof a solution of isopropylmagnesiumchloride in tetrahydrofuran (1.9M) isadded over 30 min. Subsequently 210 ml of a solution of4-biphenylmagnesiumbromide in THF (1.0M) is added over 20 min. Themixture is allowed to warm to room temperature over 19 hours. Themixture is quenched by the addition of ice-cold 2 M hydrochloric acidand the organic solvent removed under reduced pressure. To the resultingsuspension, 133 ml toluene is added and the precipitate, which iscollected by filtration, is washed with water and toluene. The filtercake is dried under reduced pressure to provide(R)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one. ¹H-NMR (DMSO): 1.93 (1H);2.17 (2H); 2.55 (1H); 5.33 (1H, dd, J=4.5, 9.6); 7.45 (1H); 7.53 (2H, t,J=7.6); 7.77 (2H, d, J=7.1); 7.89 (3H, t, J=8.5); 8.11 (2H, d, J=8.5).MS (ESI, m/e) 266 [M+H]⁺. IR (solution in CH₂Cl₂, /cm⁻¹): 3203; 3103;2880; 1699; 1684; 1604; 1407; 1238; 980; 769; 733; 698. Enantiomericexcess (ee): 99.0% (5-b, R1=H) as determined by hplc.

Example 2-3 (R)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one and(S)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one

To 32 g Mg turnings, a solution of 289 g 4-Brombiphenyl in 1100 ml THFis added. The addition of the starting 4-bromobiphenyl is done at such arate, that the reaction mixture is at reflux. After complete addition,the mixture is heated for another 1.5 h at reflux. This Grignardsolution is added then to a solution of 100 g of(R/S)-5-(morpholine-4-carbonyl)pyrrolidin-2-one in 1000 l THF at <−50°C. The cooling bath is removed and the reaction mixture is stirred overnight. The reaction mixture is then quenched with H₂O/NH₄Cl and 2M HCl.The pH of the reaction mixture is pH 8. The reaction mixture isconcentrated to a volume of 360 ml and the precipitate removed byfiltration. The precipitate is then stirred in 400 ml toluene at 70° C.and is then filtered, to yield after drying,(S)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one and(R)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one in a ratio of 64:38,respectively, as determined by hplc. 1H-NMR: (400 MHz; CDCl₃): 2.04-2.16(m, 1H), 2.26-2.45 (m, 2H), 2.54-2.67 (m, 1H), 5.08-5.13 (m, 1H),7.32-7.94 (m, 9H).

HPLC Method (Example 2):

Column: Chiralpak AS-RH (DAICEL); 150×4.6 mm; 5 μm. Mobile Phase A(water); Mobile Phase B (Acetonitrile). Isocratic: 0 min (50% B); 15 min(50% B). Flow rate: 0.8 ml min⁻¹. Wavelength: 285 nm. Temperature 25° C.

Retention Times:

5-a (R1=H): 7.1 min

5-b (R1=H): 6.5 min

Example 3-1 (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one [Key Lactam (1-a,R1=H)]

Method 1

200 mg of (S)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one of example 2 weresuspended in 3 ml THF. 20 mg of sulphuric acid and 5 mg of palladium oncarbon 10% m/m (W. C. Heraeus GmbH, Type K-0218) were added and themixture was stirred under 3 bar hydrogen for about 20 hours. The mixturewas neutralised with 50 mg sodium carbonate and the precipitate removedby filtration. The filtrate was concentrated to dryness to obtain(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one. ¹H-NMR (DMSO): 1.66 (1H, m,4-CHH); 1.94 (1H, m, 4-CHH); 2.01 (2H, m, 3-CH₂); 2.65 (1H, dd, 1-CHH);2.84 (1H, dd, 1-CHH); 3.78 (1H, m, 5-CH); 7.30 (2H, d, aromatic); 7.33(1H, m, aromatic); 7.43 (2H, t, aromatic); 7.57 (2H, d, aromatic); 7.63(2H, m, aromatic); 7.81 (1H, s, NH). m/z: 252 (MH⁺, 100%).

The X-ray Structure of the obtained crystals is shown in FIG. 1.

Crystal data [recorded at 100(2)K] Empirical formula C₁₇H₁₇NO Formulaweight 251.32 Crystal system Monoclinic Space group P21 Cell parametersa = 5.725(2) Å b = 26.815(9) Å c = 25.932(8) Å α = 90° β = 94.280(18)° γ= 90° Volume of unit cell 3970(2) Å³ Z*  12 Calculated density 1.261 mgm⁻³ *(number of asymmetric units in the unit cell)Method 2

100 g of (S)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one are suspended in860 ml THF. 2.4 g of sulphuric acid and 10 g of palladium on carbon 10%m/m (W. C. Heraeus GmbH, Type K-0218) are then added. The mixture isthen warmed to 40° C. and a pressure of 3 bar hydrogen gas applied.After 10 h, the mixture is cooled to room temperature, filtered and thefilter cake is washed with 300 ml THF. 100 ml water is added to thecombined filtrates and 21.9 g sodium hydroxide solution (2 M) is added.The mixture is then warmed to 60° C. and the volatile solvents areremoved under vacuum. The resulting suspension is filtered and the cakeis washed with 200 ml water. The solid is then added to 820 ml isopropylacetate at 65° C. and is partially concentrated. The mixture is thencooled to 3° C. and the solid collected by filtration to provide, afterdrying, (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one.

Method 3

(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (106 mg) is added to toluene(2 ml) and 10% Pd/C (10.6 mg, 10 wet wt % loading, type 394 (6249)catalyst, Johnson Matthey) is added. Hydrogen pressure is applied to 30psi and the mixture is heated to 70° C. After 16 h, the mixture iscooled to room temperature. Analysis by hplc showed 94% purity.

Method 4

(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (106 mg) is added to toluene(2 ml) and 10% Pd/C (10.6 mg, 10 wet wt % loading, type 338 catalyst,Johnson Matthey) is added. Hydrogen pressure is applied to 30 psi andthe mixture is heated to 70° C. After 16 h, the mixture is cooled toroom temperature. Analysis by hplc showed 98% purity.

Method 5

(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (106 mg) is added to toluene(2 ml) and 10% Pd/C (10.6 mg, 10 wet wt % loading, type Mod (72595)catalyst, Johnson Matthey) is added. Hydrogen pressure is applied to 30psi and the mixture is heated to 70° C. After 16 h, the mixture iscooled to room temperature. Analysis by hplc showed 96% purity.

Method 6

(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (848 mg) is added to toluene(4 ml) and 10% Pd/C (85 mg, 10 wet wt % loading, type 39 catalyst,Johnson Matthey) is added. Hydrogen pressure is applied to 30 psi andthe mixture is heated to 70° C. After 16 h, the mixture is cooled toroom temperature. Analysis by hplc showed 97% purity.

Method 7

(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (5.07 g) is added to toluene(24 ml) and 10% Pd/C (0.25 g, 5 wet wt % loading, type 39 catalyst,Johnson Matthey) is added. Hydrogen pressure is applied to 30 psi andthe mixture is heated to 70° C. After 16 h, the mixture is cooled toroom temperature. The catalyst is filtered. Product is obtained byprecipitation with heptane. Analysis by hplc showed 97% purity.

Method 8

(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (848 mg) is added to toluene(4 ml) and 10% Pd/C (85 mg, 5 wet wt % loading, type 394 (6065)catalyst, Johnson Matthey) is added. Hydrogen pressure is applied to 30psi and the mixture is heated to 70° C. After 16 h, the mixture iscooled to room temperature. Analysis by hplc showed 97% purity.

Method 9

(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (848 mg) is added to toluene(4 ml) and 10% Pd/C (42 mg, 5 wet wt % loading, type 394 (6065)catalyst, Johnson Matthey) is added. Hydrogen pressure is applied to 30psi and the mixture is heated to 70° C. After 16 h, the mixture iscooled to room temperature. Analysis by hplc showed 97% purity.

Example 3-2 (R)-5-biphenyl-4-ylmethylpyrrolidin-2-one [Key Lactam (1-b,R1=H)]

14 g of (R)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one are suspended in 80ml tetrahydrofuran. Subsequently 331 mg of concentrated sulphuric acidare added and the reaction vessel is purged with argon. 1.4 g ofpalladium on carbon 10% m/m (W. C. Heraeus GmbH, Type K-0218) is addedand the mixture is stirred under an atmosphere of hydrogen (3 bar) at30° C. for 20 h. The black suspension is filtered and the filter cake iswashed with tetrahydrofuran. After the addition of 50 ml water, the pHof the emulsion is adjusted to pH 5.5 using sodium hydroxide solution(2M). Under reduced pressure, the organic solvent is removed and 100 mlof isopropyl acetate are added. The aqueous layer is then separated andthe remaining organic layer is concentrated to approx. half of itsoriginal volume. The suspension is cooled to −5° C. and filtered. Thefilter cake is washed with cooled isopropyl acetate and is dried underreduced pressure to give (R)-5-biphenyl-4-ylmethylpyrrolidin-2-one ascolourless crystals. ¹H-NMR (CDCl₃): 1.93 (1H); 2.37 (3H); 2.80 (1H, dd,J=8.5, 13.5); 2.92 (1H, dd, J=5.4, 13.5); 3.95 (1H); 5.70 (1H); 7.29(1H, d, J=7.5); 7.38 (1H); 7.47 (2H); 7.59 (4H). MS (ESI, m/e) 252[M+H]⁺; 503 [2M+H]⁺. IR (solution in CH₂Cl₂, /cm⁻¹): 3191; 3055; 2930;1692; 1489; 1272; 762; 692.

Example 3-3 (R/S)-5-biphenyl-4-ylmethylpyrrolidin-2-one [Key Lactam (1,R1=H)]

A mixture of 26.5 g (100 mmol)(R/S)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one, 3.0 g Pd/C (10% PD CP4505 D/R Catalyst, BASF), 5 g conc. H₂SO₄ in 300 ml THF and 300 ml MeOHare hydrogenated at 1 atm pressure and heated at 50° C. After 10 h thehydrogen uptake stops. The catalyst is filtered off, washed withmethanol and the resulting filtrate is concentrated in vacuo. Theevaporation residue is dissolved in toluene and is washed with aqueousNa₂CO₃ solution. A part of the product precipitates and is filtered anddried in vacuo (96.5% HPLC area %). The toluene phase is washed twicewith H₂O and evaporated completely, to yield further crude product. Thisfurther crude product is purified over silica gel chromatography withtoluene/methanol=4:1, to yield the product. This product is stirred in70 ml toluene at 60° C. for 2 h. Then 70 ml heptanes fraction are addedand the precipitate is filtered. The precipitate is dried in vacuo toyield (R/S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (96.5% HPLC area %).¹H NMR (DMSO): 1.69 (1H), 1.96-2.05 (2H), 2.67 (1H), 2.84 (1H), 3.80(1H), 7.31 (2H), 7.44 (2H), 7.57 (2H), 7.63 (2H), 7.74 (1H).

HPLC Method 1 (Example 3):

Column: YMC-Pack ODS-AQ HP; 150×3.0 mm; 3 μm. Mobile Phase A (10 mMKH₂PO₄ in water); Mobile Phase B (Acetonitrile). Gradient: 0 min (25%B); 7 min (40% B); 10 min (40% B); 12 min (80% B); 20 min (80% B); 20.1min (25% B). Flow rate: 1.0 ml min⁻¹. Wavelength: 210 nm. Temperature45° C.

Retention Times:

13 (R1=H): 7.3 min and 7.4 min

5 (R1=H): 8.9 min

1 (R1=H): 10.9 min

HPLC Method 2 (Example 3):

Column: Chiralpak AS-RH (DAICEL); 150×4.6 mm; 5 μm. Mobile Phase A(water); Mobile Phase B (Acetonitrile). Isocratic: 0 min (60% B); 15 min(60% B).

Flow rate: 0.8 ml min⁻¹. Wavelength: 254 nm. Temperature 25° C.

1-a (R1=H): 9.9 min

1-b (R1=H): 8.3 min

Example 4(S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one(1-a, R1=pivaloyl)

Method 1

20 g of (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) of example3 were dissolved in 200 ml tetrahydrofuran. The mixture was cooled toabout −78° C. and 55 ml n-butyllithium (1.6 M) were added. After about0.5 hours, 11.8 ml of pivaloyl chloride were added. After 1 hour, themixture was quenched with 210 ml ammonium chloride solution andextracted with 70 ml ethyl acetate. The mixture was concentrated todryness to obtain 26.7 g of(S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1,R1=pivaloyl). ¹H-NMR (CDCl₃): 1.40 (9H, s, C(CH₃)₃); 1.91 (1H, m,4-CHH); 2.03 (1H, m, 4-CHH); 2.47 (1H, m, 3-CHH); 2.55 (1H, m, 3-CHH);2.74 (1H, dd, 1-CHH); 3.18 (1H, dd, 1-CHH); 4.67 (1H, m, 5-CH); 7.34(2H, m, aromatic); 7.36 (1H, m, aromatic); 7.46 (2H, m, aromatic); 7.58(4H, m, aromatic). m/z: 336 (MH⁺, 100%).

The X-ray Structure of the obtained crystals is shown in FIG. 9. Singlecrystal for this determination is obtained from diisopropylether assolvent.

Crystal data [recorded at 100(2)K] Empirical formula C₂₂H₂₅NO₂ Formulaweight 335.43 Crystal system Monoclinic Space group P21 Cell parametersa = 11.633(4) Å b = 8.486(3) Å c = 18.894(6) Å α = 90° β = 94.429(15)° γ= 90° Volume of unit cell 1859.6(11) Å³ Z*  4 Calculated density 1.198mg m⁻³ *(number of asymmetric units in the unit cell)Method 2

(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) (100 g, 398 mmol)and triethylamine (166 ml, 1.2 mol) are added to toluene (1 L) at roomtemperature. The mixture is heated to 60° C. Pivaloyl chloride (73.5 ml,597 mmol) is added over 2 h. After a further 1 h, citric acid solution(237 g in 1 L) is added and the phases are separated. The water phase iswashed with toluene (0.5 L). The organic portions are combined, washedwith water (0.5 L) and then dried (MgSO₄). The mixture is concentratedin vacuo. The residue is suspended in heptane (550 ml) and is heated toreflux. The mixture is then cooled to room temperature. After 1 h, themixture is cooled to 0° C., and then filtered to give(S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1,R1=pivaloyl)

Example 5-1(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one(2-a, R1=pivaloyl)

Method 1

0.37 ml of n-butyllithium (1.6 M) was added to a solution of 88 μldiisopropylamine in 1 ml tetrahydrofuran at about 0° C. After about 15min, 200 mg(S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one(1-a, R1=pivaloyl) of example 4 dissolved in 2 ml tetrahydrofuran wereadded. After about 15 min, 59 μl dimethylsulphate were added. Afterabout 2 hours at about 0° C., the mixture was diluted with ammoniumchloride solution, extracted with ethyl acetate and concentrated todryness (196 mg). According to HNMR analysis, the ratio ofdiastereoisomers is 83:17 [(3R,5S):(3S,5S)]. The material was purifiedby chromatography to afford 43 mg(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one=¹H-NMR(DMSO): (2-a, R1=pivaloyl) 1.07 (3H, d, 1-CH₃); 1.29 (9H, s, C(CH₃)₃);1.63 (1H, m, 4-CHH); 2.03 (1H, m, 4-CHH); 2.81 (2H, m, 3-CH, 1-CHH);2.94 (1H, dd, 1-CHH); 4.45 (1H, m, 5-CH); 7.34 (3H, m, aromatic); 7.44(2H, m, aromatic); 7.61 (4H, m, aromatic). m/z: 350 (MH⁺, 100%).Spectroscopic data for (2-b, R1=pivaloyl) as Example 5-2.

An X-ray structure of the preferred diastereoisomer (compound accordingto formula (2-a)) is shown in FIG. 2.

Crystal data [recorded at 100(2)K] Empirical formula C₂₃H₂₇NO₂ Formulaweight 349.46 Crystal system Monoclinic Space group P21 Cell parametersa = 5.645(3) Å b = 9.949(5) Å c = 17.443(9) Å α = 90° β = 91.47(3)° γ =90° Volume of unit cell 979.3(9) Å³ Z*  2 Calculated density 1.185 mgm⁻³ *(number of asymmetric units in the unit cell)Method 2

10 g of(S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one(1-a, R1=pivaloyl) were dissolved in 150 ml toluene. The mixture wascooled to about 0° C. and 71.5 ml potassium bis(trimethylsilyl)amidesolution (0.5 M in toluene) were added. After 15 min, 11 ml dimethylsulphate were added and the mixture was stirred for a further hour. Thereaction was quenched with ammonium chloride solution and extracted withethyl acetate. The combined organic phases were concentrated to drynessto obtain 15.3 g of crude(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one.According to HNMR analysis, on the crude, the ratio of diastereoisomersis 83:17 [(3R,5S):(3S,5S)]. Spectroscopic data for (2-a, R1=Pivaloyl) isreported in Example 5-1, Method 1. Spectroscopic data for (2-b,R1=Pivaloyl) is reported in Example 5-2.

Method 3

65 μl (60 mg, 0.323 mmol) dicyclohexylamine is dissolved in 1 ml dryTHF, and the solution is then cooled to 0° C. After adding 197 μl butyllithium in hexane (1.59 M), the solution is stirred at 0° C. for 15 min.A solution of 100 mg (2.84 mmol)(S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one(1-a, R1=pivaloyl) in 1 ml THF is then added drop wise and stirred at 0°C. for a further 15 min. 20 μl (47 mg, 0.328 mmol) methyl iodide is thenadded within 20 min. The resulting mixture is stirred at 0° C. for 2 h.The mixture is quenched through the addition of 2 ml saturated NH₄Clsolution, 2 ml water and 20 ml isopropyl acetate. The organic layer isseparated, dried over MgSO₄, filtered and evaporated. HPLC of theresidue reveals two methylated diastereomeric compounds 2-a (R1=Piv) and2-b (R1=Piv). Ratio (3R,5S) to (3S,5S) 85:15 as determined by hplc.

Method 4

65 μl (60 mg, 0.323 mmol) 2,2,6,6-tetramethylpiperidine is dissolved in1 ml dry THF, and the solution is then cooled to 0° C. After theaddition of 197 μl butyl lithium in hexane (1.59 M) the solution isstirred at 0° C. for 15 min. A solution of 100 mg (2.84 mmol)(S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one(1-a, R1=pivaloyl) in 1 ml THF is then added drop wise and the mixtureis stirred at 0° C. for a further 15 min. 20 μl (47 mg, 0.328 mmol)methyl iodide is then added within 20 min. The resulting mixture isstirred at 0° C. for 2.5 h. The mixture is quenched through the additionof 2 ml saturated NH₄Cl solution, 2 ml water and 20 ml isopropylacetate. The organic layer is separated, dried over MgSO₄, filtered andevaporated. HPLC of the residue reveals two methylated diastereomericcompounds 2-a (R1=Piv) and 2-b (R1=Piv); ratio (3R,5S) to (3S,5S) 88:12.

Method 5

(S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one(1-a, R1=pivaloyl) (10 g, 29.8 mmol) is dissolved in toluene (50 ml) andis cooled to 0° C. 0.5 M Potassium bis(trimethylsilyl)amide solution intoluene (77.5 ml, 38.7 mmol) is added over a period of 30 min.Dimethylsulfate (4.2 ml, 44.7 mmol) is then added over 0.5 h. After 15min, 1 M HCl (50 ml) is added and the mixture allowed to warm to roomtemperature. The phases are separated and the organic phase is washedwith 1 M NaOH (50 ml) and then with water (50 ml). Solvent is thenremoved from the organic phase in vacuo to yield a residue containingthe product. Residue contains(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one(2-a, R1=pivaloyl). Ratio (3R,5S) to (3S,5S) 86:14 as determined byhplc.

The residue is heated at reflux in methanol (50 ml). Water (5 ml) isthen added and the mixture is cooled to room temperature. After 1 h themixture is cooled to 0° C. and is stirred for a further 1 h. A solid iscollected by filtration, washed with MeOH/H₂O (5 ml, 9:1), then dried invacuo to give further purified product. Ratio (3R,5S) to (3S,5S) 84:16as determined by hplc.

Method 6

(S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one(1-a, R1=pivaloyl) (5 g, 14.9 mmol) is dissolved in toluene (25 ml) andis cooled to −10° C. 0.5 M Potassium bis(trimethylsilyl)amide solutionin toluene (38.8 ml, 19.4 mmol) is added over a period of about 30 min.Dimethylsulfate (2.1 ml, 22.4 mmol) is then added over 40 min. After 30min, saturated NH₄Cl solution (25 ml) and water (25 ml) are added.Phases are separated and the aqueous phase is washed with toluene (25ml). The combined organic phases are dried (MgSO₄). Solvent is thenremoved from the organic phase in vacuo to yield a residue containingthe product: Ratio (3R,5S) to (3S,5S) 92:8 as determined by hplc.

Method 7

(S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1,R1=pivaloyl) (10 g, 29.8 mmol) is dissolved in toluene (50 ml) and iscooled to 0° C. 0.5 M Potassium bis(trimethylsilyl)amide solution intoluene (77.5 ml, 38.7 mmol) is added over a period of 30 min.Dimethylsulfate (4.2 ml, 44.7 mmol) is then added over 0.5 h. After 15min, morpholine (2.6 ml, 29.8 mmol) is added. After 0.5 h, 1 M HCl (50ml) is added and the mixture allowed to warm to room temperature. Thephases are separated and the organic phase is washed with 1 M NaOH (50ml) and then with water (50 ml). Solvent is then removed in vacuo fromthe organic phase to yield a residue containing the product: Ratio(3R,5S) to (3S,5S) is 86:14 as determined by hplc.

The residue is heated at reflux in methanol (50 ml). Water (5 ml) isthen added and the mixture is cooled to room temperature. After 1 h themixture is cooled to 0° C. and is stirred for a further 1 h. A solid iscollected by filtration, washed with MeOH/H₂O (5 ml, 9:1) and then driedin vacuo to give a further purified solid containing the product: ratio(3R,5S) to (3S,5S) 86:14 as determined by hplc.

Method 8

(S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1,R1=pivaloyl) (5 g, 14.9 mmol) is dissolved in toluene (25 ml) and cooledto −10° C. 0.5 M Potassium bis(trimethylsilyl)amide solution in toluene(19.4 ml, 38.8 mmol) is added over a period of 30 min. Dimethylsulfate(2.1 ml, 22.4 mmol) dissolved in THF (6 ml) is then added over 20 min.After 30 min, morpholine (2.0 ml, 22.4 mmol) is added. After 1 h, 1 MHCl (50 ml) is added and the mixture allowed to warm to roomtemperature. The phases are separated and the organic phase is washedwith water (3×50 ml). Phases separated. Solvent is then removed from theorganic phase in vacuo to yield a residue containing the product: Ratio(3R,5S) to (3S,5S) 85:15 as determined by hplc.

Method 9

(S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1,R1=pivaloyl) (5 g, 14.9 mmol) is dissolved in toluene (15 ml) and iscooled to ca 0° C. 0.5 M Potassium bis(trimethylsilyl)amide solution intoluene (19.4 ml, 38.8 mmol) is added over a period of 30 min. Thismixture is then transferred over 30 min to a solution of dimethylsulfate (2.1 ml, 22.4 mmol) in toluene (2 ml) at 0° C. After 30 min,morpholine (2.0 ml, 22.4 mmol) is added. After 1 h, 1 M HCl (50 ml) isadded and the mixture allowed to warm to room temperature. The phasesare separated and the organic phase is washed with water (3×50 ml).Phases are separated and the solvent is then removed from the organicphase in vacuo to yield a residue containing the product: ratio (3R,5S)to (3S,5S) 91:9 as determined by hplc.

Method 10

(S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1,R1=pivaloyl) (5 g, 14.9 mmol) is dissolved in toluene (10 ml) and iscooled to 0° C. This solution is transferred to a vessel containing 0.5M Potassium bis(trimethylsilyl)amide solution in toluene (19.4 ml, 38.8mmol) maintained at 0° C. The mixture is then transferred over 30 min toa solution of dimethyl sulfate (2.1 ml, 22.4 mmol) in toluene (2 ml) at0° C. After 30 min, morpholine (2.0 ml, 22.4 mmol) is added. After 1 h,1 M HCl (50 ml) is added and the mixture is allowed to warm to roomtemperature. The phases are separated and the organic phase is washedwith water (3×50 ml). Phases are separated and the solvent is thenremoved from the organic phase in vacuo to yield a residue containingthe product: ratio (3R,5S) to (3S,5S) 91:9 as determined by hplc.

Method 11

(S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1,R1=pivaloyl) (10 g, 29.8 mmol) is dissolved in toluene (50 ml) and iscooled to 0° C. 0.66 M Potassium bis(trimethylsilyl)amide solution intoluene (58.6 ml, 38.7 mmol) is added over a period of about 30 min.Dimethylsulfate (4.2 ml, 44.7 mmol) is then added over 0.5 h. Afterabout 15 min, morpholine (3.9 ml, 44.7 mmol) is added. After 0.5 h, 1 MHCl (50 ml) is added and the mixture allowed to warm to roomtemperature. The phases are separated and the organic phase is washedwith 1 M NaOH (50 ml) and then with water (50 ml). Solvent is thenremoved from the organic phase in vacuo to yield a residue containingthe product: ratio (3R,5S) to (3S,5S) 87:13 as determined by hplc.

Example 5-2(3S,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one(2-b, R1=pivaloyl)

Prepared during the reaction (1) to (2) as given in Example 5-1,Method 1. Separated by chromatography eluting with 7:1 Heptane/Ethylacetate [R_(f) (2-a=0.33); (2-b=0.26)]. ¹H-NMR (DMSO): 1.10 (3H, d,CH₃); 1.29 (9H, s, C(CH₃)₃); 1.46 (1H, m, 4-CHH); 2.15 (1H, m, 4-CHH);2.57 (2H, m, 3-CH, 1-CHH); 3.19 (1H, m, 1-CHH); 4.31 (1H, m, 5-CH);7.29-7.63 (9H, 4×m, aromatic). m/z: 350 (MH⁺, 100%); 320 (11); 266 (10).

An X-ray structure of the other diastereoisomer (compound according toformula (2-b)) is shown in FIG. 3. The X-ray also shows some of compound(2-a) which co-crystallised since the sample was a mixture ofdiastereoisomers. The pure compound can, however, be obtained via columnchromatography.

Crystal data [recorded at 100(2)K] Empirical formula C₂₃H₂₇NO₂ Formulaweight 349.46 Crystal system Monoclinic Space group P21 Cell parametersa = 5.969(2) Å b = 7.678(2) Å c = 21.212(4) Å α = 90° β = 97.788(9)° γ =90° Volume of unit cell 963.2(4) Å³ Z*  2 Calculated density 1.205 mgm⁻³ *(number of asymmetric units in the unit cell)

Example 5-3(R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3,3-dimethyl-pyrrolidin-2-one

10 g(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one(2-a, R1=Piv) is added to THF (100 ml). The mixture is cooled to −30° C.Lithium diisopropylamide (17.16 ml, 2 M) is added and the mixture isstirred for 1 h. Methyl iodide (5.4 ml) is added and the mixture isstirred for 3 h. Aminoethylethanolamine (6.1 ml) is added and themixture is warmed to 40° C. and stirred for 15 min. Sulphuric acid (12g) is then added. The mixture is concentrated in vacuo and the residuetaken up in toluene. The phases are separated. The organic phase isconcentrated in vacuo and taken up in methanol (300 ml) at reflux. Oncooling, the precipitate is collected by filtration to give(R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3,3-dimethyl-pyrrolidin-2-one.¹H NMR (DMSO): 1.04 (3H), 1.15 (3H), 1.28 (9H), 1.72 (1H), 1.38 (1H),2.59 (1H), 3.14 (1H), 4.37 (1H), 7.31 (3H), 7.45 (2H), 7.62 (4H).

Example 5-4 (R)-5-Biphenyl-4-ylmethyl-3,3-dimethylpyrrolidin-2-one

6 g(R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3,3-dimethyl-pyrrolidin-2-oneis added to THF (6 ml). Lithium hydroxide (15.6 ml, 3 mol L⁻¹) is addedfollowed by tetra-butylammonium bromide (0.15 g). This mixture is thenadded to a mixture of hydrogen peroxide (4.54 g) and THF (12 ml) at 0°C. After 2.5 h, sodium bisulfite solution (12 g, 38-40%) is added. THFis removed in vacuo. Toluene (70 ml) is added and the phases separated.The organic phase is washed with water (15 ml). The phases areseparated. The organic phase is concentrated in vacuo and then heptane(60 ml) is added and the mixture cooled to 0° C.). The precipitate iscollected by filtration and dried in vacuo to give(R)-5-Biphenyl-4-ylmethyl-3,3-dimethylpyrrolidin-2-one ¹H NMR (DMSO):0.96 (3H), 0.97 (3H), 1.52 (1H), 1.78 (1H), 2.61 (1H), 2.93 (1H), 3.75(1H), 7.32 (3H), 7.45 (2H), 7.58 (2H), 7.63 (2H), 7.70 (1H).

HPLC Method (Examples 5-1 to 5-4):

Column: Gemini C6 Phenyl (Phenomenex); 150×3.0 mm; 3 μm. Mobile Phase A(0.01 M (NH₄)H₂PO₄ pH 6.6); Mobile Phase B (Acetonitrile). Gradient: 0min (40% A; 60% B); 15 min (40% A; 60% B); 20 min (20% A; 80% B); 23 min(20% A; 80% B); 23.1 min (40% A; 60% B); 26 min (40% A; 60% B). Flowrate: 0.8 ml min⁻¹. Wavelength: 254 nm.

Retention Times:

1-a (R1=H): 1.7 min

2-a (R1=H): 2.0 min

Example 5-4: 2.3 min

1-a (R1=Piv): 6.4 min

2-b (R1=Piv)=(3S,5S): 8.2 min

2-a (R1=Piv)=(3R,5S): 8.6 min

Example 5-3: 10.4 min

Ratio of diastereoisomers(3R,5S):(3S,5S)[-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one(2-a)] is determined from the peak areas of peaks for 2-a (R1=Piv) [8.6min] and 2-b (R1=Piv) [8.2 min].

Example 6 (3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-a,R1=H)

2 g(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-oneof example 5 and 2 g para-toluene sulfonic acid in 40 ml toluene wereheated under reflux for about 1 hour. Afterwards, the solution wascooled to room temperature and neutralized with 10 ml diluted aqueoussodium carbonate solution. The organic phase was separated, washed withwater and concentrated to dryness. The residue was crystallized fromiso-propyl acetate/heptane to yield 1.2 g of(3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-a, R1=H).¹H-NMR (CDCl₃): 1.90 (3H, s, CH₃); 1.83 (1H, m, 4-CHH); 2.12 (1H, m,4-CHH); 2.42 (1H, m, 3-H); 2.82 (2H, m, 1-CH₂); 3.87 (1H, m, 5-CH); 7.10(1H, s, NH); 7.26 (2H, d, aromatic); 7.34 (1H, t, aromatic); 7.43 (2H,m, aromatic); 7.54 (2H, m, aromatic); 7.58 (2H, m, aromatic). m/z: 266(MH⁺, 100%).

The X-ray Structure of the obtained crystals is shown in FIG. 7. Singlecrystal for this determination is obtained from isopropylacetate assolvent.

Crystal data [recorded at 100(2)K] Empirical formula C₁₈H₁₉NO Formulaweight 265.34 Crystal system Monoclinic Space group P21 Cell parametersa = 10.591(3) Å b = 8.832(2) Å c = 15.319(4) Å α = 90° β = 92.986(12)° γ= 90° Volume of unit cell 1431.0(6) Å³ Z*  4 Calculated density 1.232 mgm⁻³ *(number of asymmetric units in the unit cell)

Example 7 (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acidhydrochloride (3-a, R1=R2=R3=H)

5 g (3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one of example 6were mixed with a mixture of acetic acid and concentrated hydrochloricacid (50 ml ratio 1:1) and stirred under reflux for about 20 hours. Thesolution was then concentrated under vacuum and the residue crystallisedfrom acetic acid/ethyl acetate to yield 4.7 g of(2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid hydrochloride(3-a, R1=R2=R3=H). ¹H-NMR (DMSO): 1.10 (3H, s, CH₃); 1.58 (1H, m,3-CHH); 1.88 (1H, m, CHH); 2.64 (1H, m, 4-CH); 2.88 (1H, dd, 5-CHH);3.01 (1H, dd, 5-CHH); 3.45 (1H, m, 2-CH); 7.38 (3H, m, aromatic); 7.47(2H, m, aromatic); 7.66 (4H, m, aromatic); 8.07 (2H, s, NH); 12.25 (1H,s, CO₂H). m/z: 284 (MH⁺, 100%); 267 (25); 249 (47); 221 (13); 193 (24).

The X-ray Structure of the obtained crystals is shown in FIG. 5. Singlecrystal for this determination is obtained from acetonitrile/methanol assolvent.

Crystal data [recorded at 100(2)K] Empirical formula C₁₈H₂₂ClNO₂ Formulaweight 319.82 Crystal system Monoclinic Space group C2 Cell parameters a= 37.419(8) Å b = 5.587(2) Å c = 7.807(2) Å α = 90° β = 94.431(8)° γ =90° Volume of unit cell 1627.3(8) Å³ Z*  4 Calculated density 1.305 mgm⁻³ *(number of asymmetric units in the unit cell)

Example 8(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (3-a, R1=BOC, R2=R3=H)

3.2 g of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acidhydrochloride (3-a, R1=R2=R3=H) were mixed with 3.2 gdi-tert-butyl-dicarbonate, 5 g potassium carbonate and 50 mlwater/iso-propanol mixture 1:1 and stirred at room temperature for 1hour. Afterwards, the mixture was acidified with diluted phosphoricacid, extracted with iso-propyl acetate, washed with water, concentratedand crystallised from iso-propyl acetate/heptane to yield 2.8 g of(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (3-a, R1=BOC, R2=R3=H). Mpt 146-147° C.; δ_(H) (500 MHz; DMSO) 1.07(3H, d, J 7.0, 1-CH₃), 1.34 (9H, s, (CH₃)₃), 1.38 (1H, m, 3-H_(A)), 1.77(1H, m, 3-H_(B)), 2.43 (1H, m, 2-H), 2.70 (2H, d, J 7.0, 5-H), 3.69 (1H,m, 4-H), 6.74 (1H, d, J 9.0, NH), 7.27 (2H, d, J 8.0, Ar-ortho-H(Ph)),7.36 (1H, t, J 7.0, Ar-(Ph)-para-H), 7.46 (2H, t, J 7.5,Ar-(Ph)-meta-H), 7.57 (2H, d, J 8.0, Ar-meta-H(Ph), 7.64 (2H, d, J 7.5,Ar-(Ph)-ortho-H), 12.01 (1H, s, CO₂H); δ_(C) (500 MHz, DMSO) 18.1(1-CH₃), 28.3 [(CH₃)₃], 35.9 (2-C), 37.9 (3-C), 40.7 (5-C), 50.0 (4-C),77.4 [(C(CH₃)₃], 126.3, 126.5, 127.2, 128.9, 129.8 (Ar—CH), 137.7(Ar-ipso-C(Ph)), 138.3 (Ar-para-C(Ph)), 140.1 (Ar-(Ph)-ipso-C), 155.2(NCO), 177.2 (CO₂H); m/z (+ESI) 406 ([MNa]⁺, 6%), 384 ([MH]⁺, 31), 328(100), 284 (19); Found: [MH]⁺, 384.21691. C₂₃H₃₀NO₄ requires MH384.21693.

Example 9-1 (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethylester hydrochloride (3-a, R1=R2=H, R3=Et)

Method 1

150 g(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (3-a, R1=BOC, R2=R3=H) were dissolved in 1500 ml ethanol at 70° C.43 ml of thionyl chloride were then added over about 1 hour. The mixturewas then stirred for a further 2 hours. The mixture was concentrated todryness and then suspended in 3400 ml heptane. The precipitate wascollected by filtration, yielding 133 g of(2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl esterhydrochloride (3-a, R1=R2=H, R3=Et). ¹H-NMR (DMSO): 1.05 (3H, t, 1-CH₃);1.08 (3H, t, CH₂CH₃); 1.61 (1H, m, 3-CHH); 1.85 (1H, m, 3-CHH); 2.74(1H, m, 2-CH); 2.81 (1H, dd, 5-CHH); 3.08 (1H, dd, 5-CHH); 3.36 (1H, m,4-CH); 3.95 (2H, q, CH₂CH₃); 7.31 (1H, m, aromatic); 7.35 (2H, m,aromatic); 7.43 (2H, m, aromatic); 7.62 (4H, m, aromatic); 8.30 (3H, s,NH₃ ⁺). m/z 312 (MH⁺, 100%)

Method 2

150 g(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (3-a, R1=BOC, R2=R3=H) are added to 1500 ml ethanol at roomtemperature. The mixture is then warmed to an internal temperature of60-70° C. 42.8 ml Thionyl chloride is then added over a period of 1 h tothe reaction mixture. The mixture is then stirred for a further 2 h. 810ml of the solvent is removed by distillation under reduced pressure.1460 ml Heptane fraction is then added. 1310 ml of solvent is thenremoved by distillation under reduced pressure. 1460 ml Heptane fractionis then added. 520 ml of solvent is then removed by distillation underreduced pressure. 1460 ml Heptane fraction is then added. The mixture isthen cooled to room temperature over a period of 1 h. The mixture isthen stirred at room temperature for 2 h. The solid is then collected byfiltration. The solid is then washed with heptane fraction (600 ml) anddried to give (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acidethyl ester hydrochloride (3-a, R1=R2=H, R3=Et). Spectroscopic data asgiven in Example 9-1 Method 1.

Significant reflections in the X-ray diffraction pattern show thefollowing interlattice plane intervals (average 2θ in [°] are indicatedwith error limit of ±0.2): 2θ in [°]: 5.7, 6.2, 7.7, 11.3, 12.5, 17.1,22.4, 22.9. Data taken using a Bruker D8 Advance diffractometer usingCu-Kα radiation.

The X-ray Structure of the obtained crystals is shown in FIG. 6 a andFIG. 6 b. Single crystal for this determination is obtained fromacetonitrile as solvent.

Crystal data [recorded at 293(2)K] Empirical formula C₂₀H₂₆ClNO₂ Formulaweight 347.87 Crystal system Monoclinic Space group C2 Cell parameters a= 40.672(12) Å b = 6.543(2) Å c = 14.757(4) Å α = 90° β = 99.167(13)° γ= 90° Volume of unit cell 3877(2) Å³ Z*  8 Calculated density 1.192 mgm⁻³ *(number of asymmetric units in the unit cell)

Example 9-2 (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethylester hydrochloride (3-a, R1=R2=H, R3=Et)

(3-a, R1=R2=H, R3=Et) prepared in accordance Example 9-1 and iscrystallised according to the following Methods:

Method 1

500 mg (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethylester hydrochloride (3-a, R1=R2=H, R3=Et) is added to 3 ml toluene atroom temperature. The mixture is then heated to 75° C. and is stirred atthis temperature until the material has dissolved. The mixture is thencooled to room temperature and stirred for 16 h. The precipitate iscollected by filtration.

Significant reflections in the X-ray diffraction pattern show thefollowing interlattice plane intervals (average 2θ in [°] are indicatedwith error limit of ±0.2): 2θ in [°]: 16.9, 18.2, 22.2, 22.7, 24.0. Datataken using a Bruker D8 Advance diffractometer using Cu-Kα radiation.

Method 2

500 mg (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethylester hydrochloride (3-a, R1=R2=H, R3=Et) is added to 3 ml xylene atroom temperature. The mixture is then heated to 80° C. and is stirred atthis temperature until the material is dissolved. The mixture is thencooled to room temperature and stirred for 16 h. The precipitate iscollected by filtration.

Significant reflections in the X-ray diffraction pattern show thefollowing interlattice plane intervals (average 2θ in [°] are indicatedwith error limit of ±0.2): 2θ in [°]: 16.9, 18.2, 22.2, 22.7, 23.9. Datataken using a Bruker D8 Advance diffractometer using Cu-Kα radiation.

Method 3

500 mg (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethylester hydrochloride (3-a, R1=R2=H, R3=Et) is added to 5 ml ethylacetoacetate at room temperature. The mixture is then heated to 80° C.and is stirred at this temperature until the material is dissolved. Themixture is then cooled to room temperature and stirred for 16 h. Theprecipitate is collected by filtration.

Significant reflections in the X-ray diffraction pattern show thefollowing interlattice plane intervals (average 2θ in [°] are indicatedwith error limit of ±0.2): 2θ in [°]: 7.7, 17.2, 18.5, 22.4, 22.9, 24.0.Data taken using a Bruker D8 Advance diffractometer using Cu-Kαradiation.

Method 4

500 mg (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethylester hydrochloride (3-a, R1=R2=H, R3=Et) is added to 5 ml ethyl acetateat room temperature. The mixture is then heated to reflux. The mixtureis then cooled to room temperature and stirred for 16 h. The precipitateis collected by filtration. Significant reflections in the X-raydiffraction pattern show the following interlattice plane intervals(average 2θ in [°] are indicated with error limit of ±0.2): 2θ in [°]:7.5, 17.0, 18.3, 22.2, 22.8, 24.0. Data taken using a Bruker D8 Advancediffractometer using Cu-Kα radiation.

Method 5

500 mg (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethylester hydrochloride (3-a, R1=R2=H, R3=Et) is added to 5 ml xylene atroom temperature. The mixture is then heated to an external oil bathtemperature of 120° C. and is stirred at this temperature until thematerial is dissolved. The mixture is then cooled to room temperatureand stirred for 4 h The mixture is then cooled to 0° C. and stirred for1 h. The mixture is then stirred at room temperature for ca 72 h. Theprecipitate is collected by filtration.

Significant reflections in the X-ray diffraction pattern show thefollowing interlattice plane intervals (average 2θ in [°] are indicatedwith error limit of ±0.2): 2θ in [°]: 7.6, 17.1, 18.3, 19.7, 22.4, 22.8,24.0. Data taken using a Bruker D8 Advance diffractometer using Cu-Kαradiation.

Method 6

500 mg (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethylester hydrochloride (3-a, R1=R2=H, R3=Et) is added to 5 ml xylene atroom temperature. The mixture is then heated to an external oil bathtemperature of 120° C. and is stirred at this temperature until thematerial is dissolved. The mixture is then cooled slowly to roomtemperature over a period of several hours The mixture is then stirredat room temperature for 16 h. The precipitate is collected byfiltration.

Significant reflections in the X-ray diffraction pattern show thefollowing interlattice plane intervals (average 2θ in [°] are indicatedwith error limit of ±0.2): 2θ in [°]: 7.5, 17.0, 18.3, 22.3, 22.7, 24.0.Data taken using a Bruker D8 Advance diffractometer using Cu-Kαradiation.

Method 7

500 mg (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethylester hydrochloride (3-a, R1=R2=H, R3=Et) is added to 5 ml ethylacetoacetate at room temperature. The mixture is then heated to anexternal oil bath temperature of 120° C. and is stirred at thistemperature until the material is dissolved. The mixture is then cooledto room temperature and stirred for 16 h. The precipitate is collectedby filtration.

Significant reflections in the X-ray diffraction pattern show thefollowing interlattice plane intervals (average 2θ in [°] are indicatedwith error limit of ±0.2): 2θ in [°]: 7.5, 16.1, 16.9, 18.2, 20.2, 22.2,22.7, 23.9. Data taken using a Bruker D8 Advance diffractometer usingCu-Kα radiation.

Example 10 (S)-5-((S,R)-biphenyl-4-yl-hydroxymethyl)pyrrolidin-2-one(13, R1=H)

2 g of (S)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one were dissolved in 40ml THF. 200 mg Palladium on carbon were added and the mixture wasstirred under a hydrogen atmosphere for 14 hours. The removal of thecatalyst by filtration and concentration of the filtrate to drynessyielded the desired product (13) as a mixture of alcoholdiastereoisomers. ¹H NMR (CDCl₃): 1.71-2.35 (4H); 3.66-3.87 (1H); 4.45(about 0.7H) and 4.60 (about 0.3H); 5.70 (about 0.3H) and 6.24 (about0.7H); 6.85-7.66 (9H). The resulting alcohol can then be converted into(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one by using for example the sameconditions as used above in example 3. Ratio of diastereoisomers iscalculated to be 70:30 (1H NMR), based on the integrations of thesignals at 4.45 ppm (0.7H) and 4.60 (0.3H).

Example 11 (2-a, R1=pivaloyl) to (3-a, R1=R2=R3=H)

Method 1

0.5 g(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-onein 2.5 ml water, 2.5 ml concentrated hydrochloric acid and 2 ml ethylacetate were heated at about 80° C. for about 15 hours. The mixture wasevaporated to dryness to obtain(2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid hydrochloride(3-a, R1=R2=R3=H, hydrochloride salt). Spectroscopic data as reported inExample 7.

Method 2

0.5 g(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-onein 5 ml hydrobromic acid (48%) and 4 ml ethyl acetate were heated atabout 80° C. for about 15 hours. The mixture was evaporated to drynessto obtain (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acidhydrobromide (3-a, R1=R2=R3=H, hydrobromide salt). MS (ES+): 284 ([MH]⁺,100%), 267 (17), 249 (18), 221 (3), 194 (3), 193 (25), 167 (4).

Example 12 (2-a, R1=pivaloyl) to (3-a, R1=R2=H, R3=Et)

Method 1

0.5 g(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one,5 ml ethanol and 0.5 ml concentrated hydrochloric acid were heated atabout 80-120° C. for about 24 hours. The mixture was evaporated todryness to obtain (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acidethyl ester (hydrochloride salt). Spectroscopic data as reported inExample 9.

Method 2

0.5 g(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one,5 ml ethanol and 0.3 ml concentrated sulphuric acid were heated at about80-120° C. for about 24 hours. The mixture was evaporated to dryness toobtain (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethylester (hydrogen sulphate salt). Spectroscopic data as in Example 44.

Method 3

0.5 g(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one,5 ml ethanol and 0.3 ml perchloric acid were heated at about 80-120° C.for about 24 hours. The mixture was evaporated to dryness to obtain(2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester(perchlorate salt). ¹H NMR (CDCl₃): 1.17 (3H), 1.20 (3H), 1.98 (2H),2.76 (1H), 2.96 (1H), 3.29 (1H), 3.82 (1H), 3.96 (2H), 7.32-7.59 (13H),8.21 (3H).

Method 4

0.5 g(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one,5 ml ethanol and 1.1 g para-toluenesulphonic acid were heated at about80-120° C. for about 24 hours. The mixture was evaporated to dryness toobtain (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethylester (p-toluenesulphonate salt). ¹H NMR (CDCl₃): 1.08 (3H), 1.16 (3H),1.87 (1H), 1.95 (1H), 2.38 (3H), 2.77 (1H), 2.92 (1H), 3.15 (1H), 3.69(1H), 4.07 (2H), 7.16-7.77 (13H), 9.89 (3H).

Example 13 (2-a, R1=H) to (3-a, R1=R2=H, R3=Et)

Method 1

1 g (3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-a, R1=H),10 ml ethanol and 1.4 ml concentrated hydrochloric acid were heated atabout 80-120° C. for about 24 hours. The mixture was evaporated todryness to obtain (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acidethyl ester (hydrochloride salt). Spectroscopic data as reported inExample 9.

Method 2

1 g (3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-a, R1=H),10 ml ethanol and 0.4 ml concentrated sulphuric acid were heated atabout 80-120° C. for about 24 hours. The mixture was evaporated todryness to obtain (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acidethyl ester (hydrogen sulphate salt). Spectroscopic data as in Example44.

Method 3

1 g (3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-a, R1=H),10 ml ethanol and 1.4 g para-toluenesulphonic acid were heated at about80-120° C. for about 24 hours. The mixture was evaporated to dryness toobtain (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethylester (p-toluenesulfonate salt). Spectroscopic data as in Example 12.

Example 14 (2-a, R1=H) to(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (2-a, R1=BOC)

5 g (3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-a, R1=H)in solution in 50 ml ethyl acetate were mixed with 6.6 gdi-tert-butyl-dicarbonate, 3.5 g triethylamine and 1 gdimethyl-aminopyridine. After 1 hour at 50° C. the solution was mixedwith water. After separation of the layers the organic phase wasconcentrated under vacuum and diluted with heptane. The crystallinesolid obtained was collected and dried under vacuum to yield about 5.5 gof (3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (2-a, R1=BOC).

Material may be purified by column chromatography, eluting ethylacetate/heptane (6:1).

¹H-NMR (DMSO): 0.95 (3H, d, 1-CH₃); 1.42 (9H, s, C(CH₃)₃); 1.56 (1H, m,4-CHH); 1.90 (1H, m, 4-CHH); 2.50-2.57 (2H, m, 3-CH₂); 2.78 (1H, dd,1-CHH); 2.99 (1H, dd, 1-CHH); 4.14 (1H, m, 5-CH); 7.25-7.31 (3H, m,aromatic); 7.39 (2H, m, aromatic); 7.58 (4H, m, aromatic).

Example 15 (2-a, R1=BOC) to[(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid] (3-a, R1=BOC, R2=R3=H)

5 g(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (2-a, R1=BOC) was dissolved in 50 ml of a mixtureof THF and a 2 M lithium hydroxide solution (ratio 1:1). After 1 hour atroom temperature, phosphoric acid was added to neutralise the excess oflithium hydroxide. The slurry was concentrated under vacuum to removemost of the solvent and extracted with iso-propyl acetate. The organicphase was then washed with water, partially concentrated under vacuumand brought to crystallisation upon addition of heptane. The crystallinesolid obtained was collected and dried under vacuum to yield about 3.6 gof [(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid] (3-a, R1=BOC, R2=R3=H). Mpt 146-147° C.; δ_(H) (500 MHz; DMSO)1.07 (3H, d, J 7.0, 1-CH₃), 1.34 (9H, s, (CH₃)₃), 1.38 (1H, m, 3-H_(A)),1.77 (1H, m, 3-H_(B)), 2.43 (1H, m, 2-H), 2.70 (2H, d, J 7.0, 5-H), 3.69(1H, m, 4-H), 6.74 (1H, d, J 9.0, NH), 7.27 (2H, d, J 8.0,Ar-ortho-H(Ph)), 7.36 (1H, t, J 7.0, Ar-(Ph)-para-H), 7.46 (2H, t, J7.5, Ar-(Ph)-meta-H), 7.57 (2H, d, J 8.0, Ar-meta-H(Ph), 7.64 (2H, d, J7.5, Ar-(Ph)-ortho-H), 12.01 (1H, s, CO₂H); δ_(C) (500 MHz, DMSO) 18.1(1-CH₃), 28.3 [(CH₃)₃], 35.9 (2-C), 37.9 (3-C), 40.7 (5-C), 50.0 (4-C),77.4 [(C(CH₃)₃], 126.3, 126.5, 127.2, 128.9, 129.8 (Ar—CH), 137.7(Ar-ipso-C(Ph)), 138.3 (Ar-para-C(Ph)), 140.1 (Ar-(Ph)-ipso-C), 155.2(NCO), 177.2 (CO₂H); m/z (+ESI) 406 ([MNa]⁺, 6%), 384 ([MH]⁺, 31), 328(100), 284 (19); Found: [MH]⁺, 384.21691. C₂₃H₃₀NO₄ requires MH384.21693.

Example 16 (S)-5-biphenyl-4-ylmethyl-2-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (1-a, R1=BOC)

Method 1

520 mg di-tert-butyldicarbonate and 12 mg 4-(dimethylamino)pyridine wereadded to a suspension of 500 mg(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) in 3 mlacetonitrile. After about 20 hours, the mixture was concentrated todryness. The mixture was partitioned between ethyl acetate and aqueouspotassium hydrogen sulphate and the organic layer separated andevaporated to dryness to yield 630 mg of(S)-5-biphenyl-4-ylmethyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butylester (1-a, R1=BOC). ¹H-NMR (CDCl₃): 1.62 (9H, s, C(CH₃)₃); 1.88 (1H, m,4-CHH); 2.03 (1H, m, 4-CHH); 2.34-2.43 (2H, m, 3-CH₂); 2.80 (1H, dd,1-CHH); 3.21 (1H, dd, 1-CHH); 4.42 (1H, m, 5-CH); 7.28 (2H, m,aromatic); 7.76 (1H, m, aromatic); 7.46 (2H, m, aromatic); 7.59 (4H, m,aromatic). m/z: 352 (MH⁺, 14%); 337 (16); 296 (100); 293 (13); 252 (25).

The X-ray Structure of the obtained crystals is shown in FIG. 10. Singlecrystal for this determination is obtained from diethylether as solvent.

Crystal data [recorded at 100(2)K] Empirical formula C₂₂H₂₅NO₃ Formulaweight 351.43 Crystal system Monoclinic Space group P21 Cell parametersa = 5.801(2) Å b = 8.180(2) Å c = 19.891(4) Å α = 90° β = 96.278(9)° γ =90° Volume of unit cell 938.2(4) Å³ Z*  2 Calculated density 1.244 mgm⁻³ *(number of asymmetric units in the unit cell)Method 2

8.6 g (S)-5-Biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) (34.22 mmol)is dissolved in 135 ml methylene chloride. 4.2 g DMAP (34.22 mmol) isadded. The mixture is further diluted with 10 ml methylene chloride.Then 14.9 g BOC₂O (68.44 mmol) is added and further 10 ml methylenechloride is added. This reaction mixture is then stirred at reflux for7.5 h. Then a further 3.7 g BOC₂O is added. After a total reaction timeof 24 h at reflux the solvent is evaporated completely. The evaporationresidue is then filtered over 460 g of silica gel with an eluent oftoluene:ethyl acetate 4:1. The product fractions are concentrated invacuo to yield the crude product, which is recrystallised from methylenechloride/heptane fraction 1:6, to yield(S)-5-biphenyl-4-ylmethyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butylester (1-a, R1=BOC).

Method 3

(S)-5-Biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) (100 g, 398 mmol)is added to toluene (1 L) at room temperature. N,N-Dimethylaminopyridine(4.9 g, 29.8 mmol) is then added followed by triethylamine (72 ml, 517mmol). The mixture is then heated to 65° C. Di-tert-butyl dicarbonate(104 g, 478 mmol) is then added over 0.5 h. After 0.5 h, the mixture isconcentrated in vacuo. The residue is then dissolved in methanol (1 L)and warmed to 60° C. 400 ml of solvent is removed. Water (100 ml) isthen added and the mixture is cooled to room temperature. After 2 h, themixture is further cooled to 0° C. After 1 h, the mixture is filteredand the solid washed with methanol-water (5:1, 30 ml×3) mixture. Thesolid is dried in vacuo to yield(S)-5-biphenyl-4-ylmethyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butylester (1-a, R1=BOC).

Example 17(S)-5-biphenyl-4-ylmethyl-1-pyrrolidin-1-ylmethylpyrrolidin-2-one (1-a,R1=methylpyrrolidin)

A mixture of 500 mg (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a,R1=H), 329 μl pyrrolidine and 415 μl formaldehyde in 3.5 ml ethanol wereheated at reflux for 3 h. A further quantity of 164 μl pyrrolidine and148 μl formaldehyde were added and the mixture refluxed for about 24 h.The mixture was concentrated to dryness and purified by chromatographyto obtain 533 mg of(S)-5-biphenyl-4-ylmethyl-1-pyrrolidin-1-ylmethylpyrrolidin-2-one (1-a,R1=methylpyrrolidin). ¹H NMR (DMSO): 1.69 (4H, m, 2×NCH₂CH₂); 1.68-2.15(4H, m, 3-CH₂, 4-CH₂); 2.50 (4H, 2×NCH₂); 2.66 (1H, dd, 1-CHH); 3.12(1H, dd, 1-CHH); 3.94 (1H, d, NCHHN); 4.21 (1H, d, NCHHN); 7.29 (2H, d,aromatic); 7.33 (1H, t, aromatic); 7.44 (2H, t, aromatic); 7.59 (2H, d,aromatic); 7.64 (2H, d, aromatic). m/z: 335 (MH⁺, 100%)

Example 18(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (2-a, R1=BOC)

Method 1

46 μl diisopropylamine were dissolved in 2 ml tetrahydrofuran at 0° C.0.2 ml of n-butyllithium (1.6 M in hexanes) were added and the mixturestirred for about 15 min. The mixture was then cooled to −78° C. 100 mgof starting material (1-a, R1=BOC) dissolved in 1 ml tetrahydrofuranwere added. After 15 min, 71 μl methyl iodide were added and the mixturewas stirred at −78° C. for a further 5 hours. The reaction was quenchedby adding ammonium chloride solution and extracted with ethyl acetate.The organic phase was separated and concentrated to dryness to give amixture of (3R,5S):(3S,5S) diastereoisomers of 57:43, respectively.Ratio as determined by HPLC analysis. Spectroscopic data for majordiastereomer (2-a, R1=Boc) is in agreement with the data provided inExample 14 (2-a, R1=Boc).

Method 2

459 l (331 mg, 3.27 mmol) diisopropylamine is dissolved in 5 ml dry THFand is cooled to 0° C. After the addition of 1.97 ml butyl lithium inhexane (1.59 M), the solution is stirred at 0° C. for 15 min.Subsequently the reaction mixture is cooled to −78° C. and a solution of1 g (2.84 mmol) (S)-5-biphenyl-4-ylmethyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (1-a, R1=BOC), and 1.03 ml (1.09 g, 8.52 mmol)1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) in 5 ml THFare added over 15 min. After stirring for 15 min, 708 l (1.61 g, 11.38mmol) methyl iodide is added over 10 min. The resulting mixture isstirred at −78° C. for 3 h. The reaction is quenched through theaddition of 1 ml morpholine followed by 1 ml saturated NH₄Cl solutionand 15 ml isopropyl acetate. The organic phase is separated and washedwith water (3×10 ml). The organic layer is separated, dried over MgSO4,filtered and evaporated. HPLC of the residue reveals two methylateddiastereomeric compounds[(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (2-a, R1=BOC) and(3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (2-b, R1=BOC)]. ¹HNMR indicates a 50:50 ratio ofthe two diastereoisomers. (Spectroscopic data for diastereomer mixture).NMR (300 MHz, DMSO-d₆, /ppm): 7.50 (m, 4H); 7.37 (m, 2H); 7.27 (m, 1H);7.18 (m, 2H); 4.29-4.12 (m, 1H); 3.45 (m, 1H); 3.10 (m, 1H); 2.73-2.34(m, 2H); 2.17-1.97 (m, 1H); 1.54, 1.51 (2×s, 9H); 1.13, 1.09 (2×d withratio approx. 1:1, J=7.2, 7.0, 3 H). MS (ESI, m/e) 366 [M+H]⁺

Method 3

100 mg (0.284 mmol)(S)-5-biphenyl-4-ylmethyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butylester (1-a, R1=BOC) is dissolved in 2 ml THF and the solution is cooledto −78° C. Subsequently, 312 μl Lithium bis(trimethylsilyl)-amide in THF(1 M) is added over 5 min. After stirring for 15 min, 71 μl (161 mg,1.136 mmol) methyl iodide is added. The resulting mixture is stirred for5 h and then quenched with morpholine and water. According to HPLCanalysis the ratio of diastereoisomers is determined to be 67:32.

HPLC Method (1):

Column: CC 125/3 Nucleosil 10-3. Mobile Phase A (Water); Mobile Phase B(Acetonitrile). Gradient: 0 min (90% A; 10% B); 20 min (10% A; 90% B);25 min (0% A; 100% B); 25.1 min (90% A; 10% B). Flow rate: 1.0 ml min⁻¹.

Wavelength: 254 nm.

Retention Times:

1-a, R1=Boc: 14.9 min

2-a, R1=Boc and 2-b, R1=Boc:

Under these hplc conditions, no separation of 2-a, R1=Boc and 2-b,R1=Boc is observed. Consequently, the residues from the reactions aretreated with trifluoroacetic acid prior to HPLC analysis in order toremove the Boc protecting group.

Retention Times:

1-a, R1=H, 12.1 min

1-b, R1=H, 12.3 min

HPLC Method (2):

Column: Chiralpak AD-RH, 150×2.6 mm, 5.0 μm. Mobile Phase A (Water);Mobile Phase B (Acetonitrile). Isocratic: 0 min (80% B); 15 min (80% B).Flow rate: 0.5 ml min⁻¹. Wavelength: 210 nm.

Retention Times:

2-a, R1=Boc: 6.3 min

2-b, R1=Boc: 6.9 min

Example 19(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-1-pyrrolidin-1-ylmethylpyrrolidin-2-one(2-a, R1=methylpyrrolidin)

Method 1

93 μl Diisopropylamine were dissolved in 2 ml tetrahydrofuran at 0° C.0.4 ml of n-butyllithium (1.6 M in hexanes) was added and the mixturestirred for about 30 min. 200 mg of starting material (1-a,R1=methylpyrrolidin) dissolved in 1 ml tetrahydrofuran were added. After30 min, 41 μl methyl iodide were added and the mixture was stirred at 0°C. for a further 2 hours. The reaction was quenched by adding ammoniumchloride solution and extracted with ethyl acetate. The organic phasewas separated and concentrated to dryness to obtain 188 mg of crudeproduct.

According to NMR analysis the diastereomeric ratio 2-aR1=methylpyrrolidin: 2-b, R1=methylpyrrolidin is 85:15 (integrations ofsignals at 3.06 and 3.40 ppm).

¹H-NMR (DMSO, Major stereoisomer): 0.99 (3H, d, 1-CH₃); 1.55 (1H, m,4-CHH); 1.69 (4H, m, 2×NCH₂CH₂); 2.00 (1H, m, 4-CHH); 2.20 (1H, m,3-CH); 2.50 (4H, 2×NCH₂); 2.69 (1H, dd, 1-CHH); 3.06 (1H, dd, 1-CHH);3.90 (1H, m, 5-CH); 3.93 (1H, m, NCHHN); 4.22 (1H, m, NCHHN); 7.30 (2H,d, aromatic); 7.34 (1H, t, aromatic); 7.44 (2H, t, aromatic); 7.60 (2H,d, aromatic); 7.65 (2H, d, aromatic). m/z: 349 (MH⁺, 100%).

Method 2

(1-a, R1=methylpyrrolidin) (200 mg, 0.6 mmol) is dissolved in THF (3.4ml). The mixture is cooled to 0° C. Lithium bis(trimethylsilyl)amide(0.66 ml, 1M in THF) is added and the mixture is stirred for 1 h. Methyliodide (40.9 μl, 0.65 mmol) is added and the resulting mixture isstirred for 4 h at 0° C. The reaction is quenched by the addition ofsaturated ammonium chloride solution (2 ml), water (1 ml) and ethylacetate (1 ml). Phases are separated. The organic phase is washed withbrine, dried (MgSO₄) and concentrated in vacuo (222 mg crude). Accordingto NMR analysis, ratio 2-a R1=methylpyrrolidin:2-b, R1=methylpyrrolidinis 66:34.

Example 20(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-1-pyrrolidin-1-ylmethylpyrrolidin-2-one(2-a, R1=methylpyrrolidin)

(3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-a, R1=H) (1 g,3.8 mmol) is added to ethanol (7 ml). Pyrrolidine (312 μl, 3.8 mmol) andaqueous formaldehyde (393 μl, 5.3 mmol) are added. The mixture is heatedat reflux for 3 h. The mixture is next cooled to room temperature andconcentrated in vacuo to afford(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-1-pyrrolidin-1-ylmethylpyrrolidin-2-one(2-a, R1=methylpyrrolidin). Spectroscopic data as reported in Example19.

Example 21 (3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3methylpyrrolidin-2-one (2-a, R1=Piv)

(3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-a, R1=H) (500mg, 1.9 mmol) is dissolved in THF (5 ml) at room temperature. Themixture is cooled to −78° C. and then butyllithium (1.3 ml, 1.6 M) isadded. After 0.5 h, pivaloyl chloride (278 μl, 2.3 mmol) is added andthe mixture is warmed to room temperature. After 0.5 h, the mixture isdiluted with ethyl acetate and quenched by addition of saturatedammonium chloride solution followed by water. The phases are separated.The organic phase is washed with brine, dried (MgSO₄) and concentratedin vacuo The crude material is purified by column chromatography, byeluting with ethyl acetate/heptane (1:6) to give(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one(2-a, R1=Piv). Spectroscopic data as reported in Example 5-1, Method 1.

Example 22 ((S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidin-1-yl)acetonitrile(1-a, R1=cyanomethyl)

1.5 g (5.97 mmol) (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1, R₁═H) isdissolved in 15 ml dry THF and cooled to −78° C. After the addition of4.13 ml butyl lithium in hexane (1.59 M) the yellow solution is stirredat −78° C. for 30 min. Subsequently, 475 l (855 mg, 7.16 mmol)bromoacetonitrile is added and the mixture is warmed up to roomtemperature overnight. The reaction is then quenched on addition of 10ml saturated NH₄Cl solution followed by the addition of 6 ml water andthe mixture is extracted with 2×40 ml ethyl acetate. The combinedorganic layers are separated, dried over MgSO₄, filtered and evaporated.The resulting residue is purified by column chromatography(dichloromethane:methanol=99:1) to give((S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidin-1-yl)acetonitrile (1-a,R1=cyanomethyl) as off-white solid. NMR (400 MHz, DMSO-d₆, /ppm): 7.65(m, 4H); 7.47 (t, J=7.4, 2 H); 7.40 (m, 3H); 4.57 (d, J=17.7, 1H); 4.44(d, J=17.7, 1H); 3.91 (m, 1H); 3.19 (dd, J=3.9, 13.8, 1H); 2.70 (dd,J=9.2, 13.8, 1H); 2.18 (m, 2H); 1.95 (m, 1H); 1.77 (m, 1H). MS (ESI,m/e) 291 [M+H]⁺. IR (solution in CH₂Cl₂, /cm⁻¹): 3025; 2985; 2257; 1697;1688; 1486; 1421; 1323; 1271; 1182; 760; 699.

Example 23 (S)-1-Acetyl-5-biphenyl-4-ylmethyl-pyrrolidin-2-one (1-a,R1=Ac)

(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) (5 g, 19.9 mmol)is dissolved in THF (50 ml). The mixture is cooled to −78° C. andn-butyllithium (14 ml, 1.6 M) added. After 0.5 h, acetyl chloride (1.7ml, 24 mmol) is added and the mixture is allowed to warm to roomtemperature. After 1 h, the mixture is quenched with saturated ammoniumchloride (40 ml) and water (10 ml) and ethyl acetate (20 ml) are added.The organic phase is washed with brine, dried (MgSO₄) and concentratedin vacuo to give (S)-1-Acetyl-5-biphenyl-4-ylmethyl-pyrrolidin-2-one(1-a, R1=Ac). ¹H NMR (CDCl₃): 1.84 (1H), 1.93 (1H), 2.30 (1H), 2.32(1H), 2.50 (3H), 2.72 (1H), 3.09 (1H), 4.56 (1H), 7.20 (2H), 7.28 (1H),7.37 (2H), 7.49 (4H).

Example 24 (S)-5-Biphenyl-4-ylmethyl-1-triethylsilanyl-pyrrolidin-2-one(1-a, R1=TES)

A dry flask is charged with 1.256 g (5 mmol)(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) and 15 ml dry THF.To the resulting clear solution, 2.02 g (20 mmol) triethylamine is addedfollowed by 904 mg (6 mmol) triethylchlorosilane (TES-Cl). The reactionmixture is stirred at room temperature for 4 h and then quenched onaddition of 5 ml saturated NaHCO₃ solution, 10 ml water and 10 mlisopropyl acetate. The layers are separated and the aqueous layerextracted with 10 ml isopropyl acetate. The combined organic layers aredried over MgSO₄, filtered and evaporated. The resulting residue ispurified by column chromatography (dichloromethane+1% v/v triethylamine)to give (S)-5-Biphenyl-4-ylmethyl-1-triethylsilanyl-pyrrolidin-2-one(1-a, R1=TES) as a yellow oil. NMR (300 MHz, DMSO-d₆, /ppm): 7.63 (m,4H); 7.55 (m, 2H); 7.32 (m, 3H); 3.80 (m, 1H); 2.85 (m, 1H), 2.70 (m,1H), 2.10-1.70 (m, 4H), 1.02-0.80 (m, 15H). MS (ESI, m/e) 366 [M+H]⁺;731 [2M+H]⁺. IR (solution in CH₂Cl₂, /cm⁻¹): 3426; 3047; 2957; 1698;1672; 1487; 1378; 1242; 1114; 1008.

Example 25(3R,5S)-5-Biphenyl-4-ylmethyl-3-methyl-1-triethylsilanyl-pyrrolidin-2-one(2-a, R1=TES) and(3S,5S)-5-Biphenyl-4-ylmethyl-3-methyl-1-triethylsilanyl-pyrrolidin-2-one(2-b, R1=TES)

109 mg (0.2981 mmol)(S)-5-Biphenyl-4-ylmethyl-1-triethylsilanyl-pyrrolidin-2-one (1-a,R1=TES) is dissolved in 1.5 ml toluene and the solution is cooled to 0°C. After slow addition of 628 l potassium-bis-(trimethylsilyl)-amide intoluene (0.57 M), the solution is stirred at 0° C. for 15 min.Subsequently, 113 l (150 mg, 1.19 mmol) dimethylsulfate is added to thesuspension over 5 min. The mixture is then stirred at 0° C. for 1 h. Thereaction is quenched by addition of 2 ml saturated NH₄Cl solution, 2 mlwater followed by 20 ml isopropyl acetate. The organic phase is washedwith water (3×10 ml), separated, dried over MgSO₄, filtered andevaporated. HPLC of the residue reveals conversion to the two methylateddiastereomeric compounds[(3R,5S)-5-Biphenyl-4-ylmethyl-3-methyl-1-triethylsilanyl-pyrrolidin-2-one(2-a, R1=TES) and(3S,5S)-5-Biphenyl-4-ylmethyl-3-methyl-1-triethylsilanyl-pyrrolidin-2-one(2-b, R1=TES)].

Example 26 (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acidbenzyl ester (1-a, R1=Cbz)

1 g (4 mmol) (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) isdissolved in 10 ml dry THF and cooled to −78° C. After the addition of2.76 ml butyl lithium in hexane (1.59 M), the yellow solution is stirredat −78° C. for 30 min. Subsequently, 676 l (820 mg, 4.8 mmol) benzylchloroformate (Cbz-Cl) is added and stirring is continued at −78° C. for2 h. The reaction is then quenched by addition of 12 ml saturated NH₄Clsolution followed by 10 ml water and then extracted with 2×40 mlisopropyl acetate. The layers are separated and the organic layer isdried over MgSO₄, filtered and evaporated. The resulting residue (1.73g) is purified on column chromatography(dichloromethane:methanol=99.5:0.5) to give(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid benzylester (1-a, R1=Cbz) as off-white solid. NMR (400 MHz, DMSO-d₆, /ppm):7.66 (m, 2H); 7.60 (m, 2H); 7.51-7.34 (m, 8H); 7.26 (d, J=8.2, 2 H);5.28 (s, 2H); 4.37 (m, 1H); 3.05 (dd, J=3.3, 13.1, 1H); 2.88 (dd, J=9.0,13.1, 1H); 2.45 (m, 1H); 2.28 (m, 1H); 2.01 (m, 1H); 1.77 (m, 1H). MS(ESI, m/e) 386 [M+H]⁺, 788 [2M+NH₄ ⁺]. IR (solution in CH₂Cl₂, /cm⁻¹):3092; 2957; 1756; 1705; 1488; 1396; 1304; 1287; 1231; 1139; 1043; 952;750.

Example 27(3R,5S)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid benzyl ester (2-a, R1=Cbz) and(3S,5S)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid benzyl ester (2-b, R1=Cbz)

Method 1

119 mg (0.309 mmol)(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid benzylester (1a, R1=Cbz) is dissolved in 1.5 ml toluene and the solution iscooled to −78° C. After the addition of 665 lpotassium-bis-(trimethylsilyl)-amide in toluene (0.57 M) the solution isstirred at −75° C. for 20 min. Subsequently, 117 l (155 mg, 1.23 mmol)dimethylsulfate is added to the orange solution over 5 min. Theresulting mixture is stirred at −78° C. for 3 h and then warmed to 0° C.over 1 h. The reaction is then quenched by addition of 2 ml saturatedNH₄Cl solution, 2 ml water followed by the addition of 20 ml isopropylacetate. The organic phase is washed with water (3×10 ml), dried overMgSO₄, filtered and evaporated. HPLC and LC-MS of the residue revealsthe two methylated diastereomeric compounds[(3R,5S)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid benzyl ester (2-a, R1=Cbz) and(3S,5S)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid benzyl ester (2-b, R1=Cbz)], which were inseparable from oneanother MS (ESI): 399 [MH]⁺, 816 [2M+NH₄]⁺.

Method 2

53 l (38 mg, 0.379 mmol) diisopropylamine is dissolved in 1 ml dry THFand is cooled to 0° C. After the addition of 226 l butyl lithium inhexane (1.59 M), the solution is stirred at 0° C. for 10 min.Subsequently, a solution of(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid benzylester (1-a, R1=Cbz) in 1 ml THF is added over 10 min followed by theaddition of 24 l (54 mg, 0.379 mmol) methyl iodide over 5 min. Theresulting mixture is stirred at 0° C. for 2 h. Then, the reaction isquenched by addition of 2 ml saturated NH₄Cl solution, 1 ml water and 5ml ethyl acetate. The organic phase is separated and then washed withwater (3×5 ml). The organic layer is then dried over MgSO4, filtered andevaporated. HPLC and LC-MS of the residue reveals the two methylateddiastereomeric compounds[(3R,5S)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid benzyl ester (2-a, R1=Cbz) and(3S,5S)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylicacid benzyl ester (2-b, R1=Cbz)], which were inseparable from oneanother.

Example 28(S)-5-Biphenyl-4-ylmethyl-1-(2-trimethylsilanylethoxymethyl)pyrrolidin-2-one(1-a, R1=SEM)

804 mg (3.2 mmol) (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H)is dissolved in 16 ml dry THF and cooled to −78° C. After the additionof 2.21 ml butyl lithium in hexane (1.59 M), the yellow solution isstirred at −78° C. for 30 min. Subsequently, 680 l (640 mg=3.84 mmol)(2-chloromethoxyethyl)-trimethylsilane (SEM-Cl) is added and stirring iscontinued at −20° C. for 5 h. The mixture is then allowed to warm up toroom temperature overnight. The reaction is then quenched by addition of10 ml saturated NH₄Cl solution followed by 10 ml water and extractedwith 2×40 ml isopropyl acetate. The layers are separated and the organiclayer dried over MgSO₄, filtered and evaporated. The resulting residue(1.33 g) is purified using column chromatography(dichloromethane:triethylamine=99.5:0.5→dichloromethane:methanol:triethylamine=98.5:1:0.5)to give(S)-5-Biphenyl-4-ylmethyl-1-(2-trimethylsilanylethoxymethyl)pyrrolidin-2-one(1-a, R1=SEM) as a yellow oil. NMR (400 MHz, CDCl₃, /ppm): 7.58 (m, 4H);7.47 (m, 2H); 7.37 (m, 1H); 7.30 (m, 2H); 5.04 (d, J=10.6, 1H); 4.70 (d,J=10.6, 1 H); 4.03 (m, 1H); 3.59 (m, 2H); 3.24 (dd, J=4.2, 13.4, 1H);2.67 (dd, J=9.1, 13.4, 1H); 2.33 (t, J=8.2, 2 H); 2.10 (m, 1H); 1.81 (m,1H); 1.00 (m, 2H); 0.06 (s, 9H). MS (ESI, m/e) 382 [M+H]⁺; 763 [2M+H]⁺.IR (solution in CH₂Cl₂, /cm⁻¹): 3057; 2951; 1702; 1487; 1414; 1249;1073; 859; 836; 759; 697.

Example 29(3R,5S)-5-Biphenyl-4-ylmethyl-3-methyl-1-(2-trimethylsilanylethoxymethyl)pyrrolidin-2-one(2-a, R1=SEM) and(3S,5S)-5-Biphenyl-4-ylmethyl-3-methyl-1-(2-trimethylsilanylethoxymethyl)pyrrolidin-2-one(2-b, R1=SEM)

118 mg (0.309 mmol)(S)-5-Biphenyl-4-ylmethyl-1-(2-trimethylsilanylethoxymethyl)pyrrolidin-2-one(1-a, R1=SEM) is dissolved in 1.5 ml toluene and the solution is cooledto 0° C. with an ice bath. After the slow addition of 664 lpotassium-bis-(trimethylsilyl)-amide in toluene (0.57 M), the solutionis stirred at 0° C. for 15 min. Subsequently, 114 l (151 mg, 1.2 mmol)dimethylsulfate is added to the orange solution over 5 min. Theresulting mixture is stirred at 0° C. for 2 h. Then, the reaction isquenched by addition of 2 ml saturated NH₄Cl solution, 2 ml water, and20 ml isopropyl acetate. The organic phase is separated, washed withwater (3×10 ml), dried over MgSO₄, filtered and evaporated. HPLC of theresidue (100 mg) reveals the two methylated diastereomeric compoundsR3R,5S)-5-Biphenyl-4-ylmethyl-3-methyl-1-(2-trimethylsilanylethoxymethyl)pyrrolidin-2-one(2-a, R1=SEM) and(3S,5S)-5-Biphenyl-4-ylmethyl-3-methyl-1-(2-trimethylsilanylethoxymethyl)pyrrolidin-2-one(2-b, R1=SEM)] and 25% unchanged starting material(S)-5-Biphenyl-4-ylmethyl-1-(2-trimethylsilanylethoxymethyl)pyrrolidin-2-one(1-a, R1=SEM). NMR analysis indicates an 80:20 ratio ofdiastereoisomers. (Spectroscopic data for the mixture) NMR (300 MHz,CDCl₃, /ppm): 7.58 (m, 4H); 7.47 (m, 2H); 7.35 (m, 1H); 7.25 (m, 2H);5.00 (m, 1H); 4.63 (m, 1H); 3.96 (m, 1H); 3.55 (m, 2H); 3.15 (m, 1H);2.60 (m, 1H); 2.30 (m, 1H); 2.05 (m, 1H); 1.65 (m, 1H); 1.16, 1.13 (2×dwith ratio 2:8, J=7.2, 7.0, 3 H); 0.90 (m, 2H); 0.06 (s, 9H). MS (ESI,m/e) 395 [M+H]⁺, 791 [2M+H]⁺.

Example 30 (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one [Key Lactam (1-a,R1=H)]

11 g of Mg turnings (452 mmol) are placed into a reactor. A solution of93.2 g 4-bromobiphenyl (400 mmol), dissolved in 380 ml THF is added.Formation of the corresponding Grignard reagent starts after theaddition of 5% of the total volume of the above solution and after theaddition of a 10 mg I₂. The THF solution of the 4-bromobiphenyl is addedat such a rate, that the IT can be kept at 50-55° C. (duration of theaddition: 1 h). After the addition is complete, the reaction mixture isheated to reflux for 1.5 h. Then the mixture is cooled to rt, and next800 ml THF are added, followed by 22 g 1,4-dioxane. Then the mixture iscooled in an ice bath and 18.0 g CuCN (200 mmol) are added. The reactionmixture is then cooled to −40° C. and then over 40 minutes a solution of27 g (100 mmol) toluene-4-sulphonic acid-(S)-5-oxo-pyrrolidin-2-ylmethylester in 270 ml THF is added. After complete addition of the tosylatesolution, the mixture is heated for 0.5 h to IT 35° C. The reactionmixture is stirred at that temperature overnight. Then, the reactionmixture is cooled to 20° C. and 200 ml 25% NH₃ (aq), followed by 900 mlNH₄C129% (aq) are added. The phases are separated and the aqueous phaseis re-extracted with 250 ml THF. The combined organic phases are washedtwice with 200 ml 15% NaCl solution and are concentrated in vacuo togive 74.5 g of crude product. This crude product is purified twice oversilica gel (eluent: toluene:methanol 93:7), to yield(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one [Key Lactam (1-a, R1=H)]Spectroscopic data as in Example 3.

Example 31 (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one [Key Lactam (1-a,R1=H)]

(S)-5-Iodomethylpyrrolidin-2-one (225 mg) is added to a solution ofanhydrous iron(III) chloride (9.5 ml, 0.1 M in THF). The mixture is thencooled to 0° C. Biphenylmagnesium bromide (5 ml, 0.5 M in THF) and TMEDA(180 μl) are added dropwise over 0.5 h. The mixture is stirred for afurther 10 min. Water (2 ml) is added. The mixture is extracted usingdichloromethane (3×5 ml). The combined organic extracts are washed with2 M HCl (2×5 ml), dried (Na₂SO₄), and then concentrated in vacuo.Purification by column chromatography provides(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one [Key Lactam (1-a, R1=H)].Spectroscopic data as in Example 3.

Example 32 (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one [Key Lactam (1-a,R1=H)]

8.9 g of (S)-5-biphenyl-4-ylmethyl-2-oxo-pyrrolidine-1-carboxylic acidtert-butyl ester (1-a, R1=BOC) (25.3 mmol) is dissolved in 90 mlmethylene chloride. Then 5 ml CF₃COOH are added. This mixture is stirredat rt for 1.5 h. The reaction mixture is concentrated. Heptane fractionis then added to the residue. The product is crystallized. The obtainedproduct is dissolved in toluene and then it is washed with NaHCO₃ (aq)solution. The organic layer is evaporated to yield(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one [Key Lactam (1-a, R1=H)].Spectroscopic data as in Example 3.

Example 33 (S)-1-Benzyl-5-biphenyl-4-ylmethyl-pyrrolidin-2-one (1-a,R1=Bn)

6.1 g of (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one [Key Lactam (1-a,R1=H)] (24 mmol) is dissolved in 100 ml THF. Then 4.5 g of benzylbromide are added. This mixture is cooled in in ice bath and 1.2 g NaHis added. The ice bath is removed and the reaction mixture is stirredovernight at rt. Then 50 ml H₂O is added. Toluene is added and thephases are separated. The combined organic phases are washed with H₂Oand the solvent is evaporated under reduce pressure. The crude productis purified by column chromatography on 150 g silica gel, to yield(S)-1-Benzyl-5-biphenyl-4-ylmethyl-pyrrolidin-2-one (1-a, R1=Bn). ¹H NMR(400 MHz, DMSO): 1.79 (1H), 1.93 (1H), 2.31 (2H), 2.61 (1H), 3.03 (1H),3.69 (1H), 4.02 (1H), 5.10 (1H), 7.12 (2H), 7.26 (2H), 7.33 (4H), 7.42(2H), 7.49 (2H), 7.56 (2H).

Example 34(3R,5S)-1-Benzyl-5-biphenyl-4-ylmethyl-3-methyl-pyrrolidin-2-one (2-a,R1=Bn)

Method 1

Under Ar, 15 ml 1 M LiN(TMS)₂ are added to 20 ml THF. This solution iscooled to −78° C. Then over 10 minutes a solution of 3.6 g(S)-1-Benzyl-5-biphenyl-4-ylmethyl-pyrrolidin-2-one (1-a, R1=Bn) in 20ml THF is added at −78° C. The addition funnel is rinsed with 3 ml THF.The mixture is heated to 0° C. and stirred for 10 minutes at thattemperature. Then the reaction mixture is cooled down to −78° C. andover 5 minutes a solution of 1.87 g methyl iodide in 0.5 ml THF isadded. The addition funnel is rinsed with 0.5 ml THF. This reactionmixture is stirred for 18 h at −78° C. Then it is quenched by theaddition of 18 ml saturated NH₄Cl (aq) solution. Then 36 ml toluene isadded, followed by 9 ml H₂O. The phases are separated. The aqueous phaseis re-extracted with 10 ml toluene and the combined organic phases arewashed twice with 25 ml of H₂O. The solvent is evaporated under reducedpressure, to yield the crude product. NMR analysis reveals a mixture ofdiasteromers 77:33 (2-a, R1=Bn/2-b, R1=Bn). Purification by columnchromatography on silica gel with ethyl acetate:heptane fraction (4:6)provides(3R,5S)-1-Benzyl-5-biphenyl-4-ylmethyl-3-methyl-pyrrolidin-2-one (2-a,R1=Bn). ¹H NMR (400 MHz, CDCl₃): 1.20 (3H), 1.59 (1H), 2.07 (1H), 2.40(1H), 2.66 (1H), 2.99 (1H), 3.63 (1H), 4.02 (1H), 5.11 (1H), 7.14 (2H),7.24 (2H), 7.33 (4H), 7.43 (2H), 7.50 (2H), 7.56 (2H).

Method 2

Reaction is performed in accordance with the procedure given in Method 1with the following change: after addition of methyl iodide and rinsingof the funnel with THF, the mixture is stirred for 4 h at −78° C. asappose to the 18 h indicated in Method 1. The reaction is quenched andworked up using the same conditions employed in Method 1. Under suchconditions, on the basis of NMR analysis, the ratio of diastereoisomersis 88:12 (2-a, R1=Bn/2-b, R1=Bn).

Example 35(E/Z)—(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylaminopent-2-enoic acidethyl ester (8-a, R1=Boc, R2=H, R5=Et)

To a solution of 159 g of (2-biphenyl-4-yl-1-formyl-ethyl)carbamic acidtert-butyl ester (7-a, R1=Boc, R1=H) in isopropyl acetate (3.2 L) isadded ethyl(triphenylphosphoranylidene)acetate (199 g). The mixture isstirred for 2 hours. To the mixture is added a solution of citric acid(79 g) in water (400 ml). After 1 hour, the phases are separated and theorganic phase concentrated to dryness. The crude mixture is purified bychromatography (heptane/ethyl acetate) to give(E/Z)—(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylaminopent-2-enoic acidethyl ester (8-a, R1=Boc, R2=H, R5=Et) as a mixture of cis and transisomers. ¹H NMR (DMSO) major (trans double bond isomer): 1.19 (3H, t,CH₃); 1.30 (9H, s, C(CH₃)₃); 2.74 (1H, m, 5-CHH); 2.90 (1H, dd, 5-CHH);4.11 (2H, m, CH₂CH₃); 4.41 (1H, m, 4-CH); 5.85 (1H, d, 2-CH); 6.89 (1H,dd, 3-CH); 7.32 (3H, m, aromatic); 7.43 (2H, m, aromatic); 7.57 (2H, m,aromatic); 7.62 (2H, m, aromatic). m/z: 413 (MNH₄ ⁺, 100%), 396 (MH⁺,17); 340 (60); 296 (96); 250 (11).

Example 36 (S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylaminopentanoic acidethyl ester [9-a, R1=Boc, R2=H, R5=Et]

115 g of(E/Z)—(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylaminopent-2-enoic acidethyl ester (8-a, R1=Boc, R2=H, R5=Et) is dissolved in isopropyl acetate(1.2 L). Palladium on carbon (10% loading; 11.5 g) is added and hydrogengas is applied to the vessel. After about 1 h, the vessel is purged withargon and the catalyst is removed by filtration. The solution isconcentrated to dryness, affording(S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylaminopentanoic acid ethyl ester[9-a, R1=Boc, R2=H, R5=Et]. ¹H-NMR (DMSO): 1.14 (3H, t, CH₃); 1.31 (9H,s, C(CH₃)₃); 1.56 (1H, m, 3-CHH); 1.71 (1H, m, 3-CHH); 2.28 (2H, m,2-CH₂); 2.69 (2H, m, 5-CH₂); 3.62 (1H, m, 4-CH); 4.01 (2H, q, CH₂CH₃);6.75 (1H, d, NH); 7.25 (2H, d, aromatic); 7.33 (1H, t, aromatic); 7.43(2H, t, aromatic); 7.55 (2H, t, aromatic); 7.62 (2H, t, aromatic). m/z:398 (MH⁺, 100%); 342 (52); 298 (59).

Example 37 (S)-4-Amino-5-biphenyl-4-yl-pentanoic acid ethyl esterhydrochloride [10-a, R5=Et]

To a solution of (S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylaminopentanoicacid ethyl ester [9-a, R1=Boc, R2=H, R5=Et] (115 g) in ethanol (1.1 L)at 70° C. is added thionyl chloride (32 ml) over 45 min. After a further1.5 hours, the mixture is concentrated to dryness. The crude material issuspended in ethyl acetate and filtered to give(S)-4-Amino-5-biphenyl-4-yl-pentanoic acid ethyl ester hydrochloride[10-a, R5=Et]. ¹H NMR (DMSO): 1.08 (3H, d, CH₃); 1.73 (2H, m, 3-CH₂);2.35-2.52 (2H, m, 2-CH₂); 2.79 (1H, dd, 5-CHH); 2.97 (1H, dd, CHH); 3.38(1H, m, 4-CH); 3.97 (2H, q, CH₂CH₃); 7.30 (3H, m, aromatic); 7.40 (2H,m, aromatic); 7.58 (4H, m, aromatic); 8.15 (3H, s, NH₃ ⁺). m/z: 298(MH⁺, 100%); 281 (4); 235 (3).

The X-ray Structure of the obtained crystals is shown in FIG. 11. Singlecrystal for this determination is obtained from methanol as solvent.

Crystal data [recorded at 100(2)K] Empirical formula C₁₉H₂₄ClNO₂ Formulaweight 333.84 Crystal system Orthorhombic Space group P212121 Cellparameters a = 5.307(2) Å b = 16.570(4) Å c = 39.778(10) Å α = 90° β =90° γ = 90° Volume of unit cell 3498.0(18) Å³ Z*  8 Calculated density1.268 mg m⁻³ *(number of asymmetric units in the unit cell)

Example 38 (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one [Key Lactam (1-a,R1=H)]

To a mixture of (S)-4-Amino-5-biphenyl-4-yl-pentanoic acid ethyl esterhydrochloride [10-a, R5=Et] (86 g) in isopropyl acetate (1 L) is addedtriethylamine (43 g). The mixture is then stirred at about 55° C. for 1h and then filtered. The filtrate is heated at reflux for 24 hours. Tothe mixture is added saturated ammonium chloride solution and the phasesare separated. The organic layer is concentrated to dryness andcrystallized from isopropyl acetate to yield(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one [Key Lactam (1-a, R1=H)].Spectroscopic data agree with data provided above.

Example 39(2R,4S)-5-Biphenyl-4-yl-4-[3-(2-bromoethoxycarbonyl)-propionylamino]-2-methylpentanoicacid (3-a, R1=4-oxo-pentanoic acid 2-bromoethyl ester, R2=H, R3=Et)

(2R,4S)-5-Biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methylpentanoicacid ethyl ester (3-a, R1=4-oxo-pentanoic acid, R2=H, R3=Et) (5.5 g) isdissolved in toluene (33 ml) at room temperature. Dimethylformamide (0.1ml) is added. Thionyl chloride (2.4 ml) is then added. The solution iscooled to 0° C. and 2-bromoethanol (0.94 ml) is added. The mixture isstirred at 0° C. for 2 h and then at room temperature for a further 1 h.A further portion of 2-bromoethanol (0.94 ml) is added and the mixturestirred for 0.5 h at room temperature. A further portion of2-bromoethanol (0.94 ml) is then added and the resulting mixture stirredfor 16 h at room temperature. The mixture is concentrated in vacuo togive the crude product. Purification by chromatography Heptane/EtOAc(2:1) gives(2R,4S)-5-Biphenyl-4-yl-4-[3-(2-bromoethoxycarbonyl)propionylamino]-2-methylpentanoicacid (3-a, R1=4-oxo-pentanoic acid 2-bromoethyl ester, R2=H, R3=Et). ¹HNMR (DMSO): 1.07 (3H), 1.14 (3H), 1.41 (1H), 1.79 (1H), 2.37 (2H), 2.48(1H), 2.50 (2H), 2.71 (2H), 3.66 (2H), 3.94 (1H), 3.99 (2H), 4.33 (2H),7.25 (2H), 7.35 (1H), 7.46 (2H), 7.57 (2H), 7.64 (2H), 7.78 (1H).

Example 40(2R,4S)-5-Biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoicacid ethyl ester

(2R,4S)-5-Biphenyl-4-yl-4-[3-(2-bromoethoxycarbonyl)propionylamino]-2-methylpentanoicacid (3-a, R1=4-oxo-pentanoic acid 2-bromoethyl ester, R2=H, R3=Et) (6g, 11.6 mmol) is dissolved in DMF (30 ml). Cesium carbonate (8.2 g, 23.2mmol) is added and mixture is stirred at 50° C. for 2 h. Water (150 ml)is then added followed by addition of ethyl acetate (150 ml). Next, thephases are separated. The organic phase is washed with brine, dried(Na₂SO₄) and concentrated in vacuo. The mixture is purified bychromatography: Heptane/EtOAc (2:1) to afford(2R,4S)-5-Biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoicacid ethyl ester. ¹H NMR (DMSO): 1.05 (3H), 1.14 (3H), 1.94 (1H), 2.20(1H), 2.39 (1H). 2.51 (4H), 2.98 (1H), 3.12 (1H), 4.01 (2H), 4.29 (1H),7.18 (2H), 7.32 (1H), 7.43 (2H), 7.56 (2H), 7.62 (2H).

Example 41(2R,4S)-5-Biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methyl-pentanoicacid (3-a, R1=4-oxo-pentanoic acid, R2=H, R3=H)

(2R,4S)-5-Biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoicacid ethyl ester (590 mg) is added to a mixture of 1 M NaOH (2.75 ml),THF (9 ml) and ethanol (9 ml). The mixture is stirred for 16 h. Themixture is diluted with water (20 ml) and extracted with isopropylacetate. The water phase is acidified with 1 M HCl (5 ml) and extractedwith isopropyl acetate. The combined organic phases are dried (MgSO₄)and concentrated in vacuo to give(2R,4S)-5-Biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methyl-pentanoicacid (3-a, R1=4-oxo-pentanoic acid, R2=H, R3=H). ¹H NMR (DMSO): 1.05(2H), 1.35 (1H), 1.79 (1H), 2.29 (2H), 2.39 (3H), 2.70 (2H), 3.97 (1H),7.25 (2H), 7.34 (1H), 7.44 (2H), 7.56 (2H), 7.63 (2H), 7.74 (1H), 12.01(2H).

Example 42(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid ethyl ester (3-a, R1=BOC, R2=H, R3=Et)

50 g of(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (3-a, R1=BOC, R2=R3=H) is added to dimethylformamide (80 ml).Cesium carbonate (69 g) is then added. Ethyl iodide (13.6 g) is thenadded and the mixture is stirred overnight at room temperature. Water(200 ml) is added to the mixture and the mixture is then extracted withisopropyl acetate (2×200 ml). The combined organic phases are washedwith brine, dried (MgSO₄) and concentrated in vacuo to give(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid ethyl ester (3-a, R1=BOC, R2=H, R3=Et) (56 g). ¹H NMR (DMSO): 1.12(3H), 1.19 (3H), 1.36 (9H), 1.53 (1H), 1.84 (1H), 2.55 (1H), 2.75 (2H),3.74 (1H), 4.05 (2H), 6.04 (1H), 7.23 (2H), 7.30 (1H), 7.41 (2H), 7.50(2H), 7.57 (2H). m/z (ES+): 412 ([MH]⁺, 100%), 356 (63), 312 (73).

Example 43 (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethylester hydrobromide (3-a, R1=R2=H, R3=Et)

10 g(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (3-a, R1=BOC, R2=R3=H) are added to ethanol (100 ml). The mixtureis heated to 65° C. 3 ml of thionyl bromide is then added over 0.5 hour.The mixture is then stirred for a further 1 hour. The ethanol is removedand heptane added. Further azeotropic distillations are performed usingheptane to remove any residual ethanol. The solvent is removed in vacuoto afford (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethylester hydrobromide (3-a, R1=R2=H, R3=Et). ¹H NMR (DMSO): 1.11 (6H), 1.61(1H), 1.87 (1H), 2.73 (1H), 2.84 (1H), 3.04 (1H), 3.42 (1H), 4.01 (2H),7.36 (3H), 7.47 (2H), 7.65 (4H), 8.03 (3H). m/z (ES+) 312 ([MH]⁺, 100%).

Example 44 (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethylester hydrogen sulphate (3-a, R1=R2=H, R3=Et)

10 g(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (3-a, R1=BOC, R2=R3=H) are added to ethanol (100 ml). The mixtureis heated to 65° C. 2 ml of concentrated sulphuric acid is then addedover 0.5 h. The mixture is then stirred overnight. The ethanol isremoved and heptane added. Further azeotropic distillations areperformed using heptane to remove any residual ethanol. The solvent isremoved in vacuo to afford(2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl esterhydrogen sulphate (3-a, R1=R2=H, R3=Et). ¹H NMR (DMSO): 1.12 (6H), 1.56(1H), 1.87 (1H), 2.67 (1H), 2.78 (1H), 2.98 (1H), 3.76 (2H), 7.34 (3H),7.47 (2H), 7.64 (4H), 8.57 (3H). m/z (ES+) 312 ([MH]⁺, 100.

Example 45 (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acidhydrochloride (3-a, R1=R2=R3=H)

A mixture of 37% hydrochloric acid (85 ml), ethyl acetate (100 ml) andwater (100 ml) is heated to an external oil bath temperature of 130° C.50 g(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoicacid (3-a, R1=BOC, R2=R3=H) in ethyl acetate (100 ml) is then added tothe mixture over 45 min. The mixture is stirred for a further 1 h. Themixture is then cooled to 0° C. and the solid collected by filtration togive (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acidhydrochloride (3-a, R1=R2=R3=H). Spectroscopic data as given in Example7.

Example 46(2R,4S)-5-Biphenyl-4-yl-4-(2,2-dimethylpropionylamino)-2-methylpentanoicacid ethyl ester (3-a, R1=Piv, R2=H, R3=Et)

10 g (2S,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl esterhydrochloride (3-a, R1=R2=H, R3=Et) in isopropyl acetate (50 ml) isadded to a mixture of pivaloyl chloride (4.1 ml) in isopropyl acetate(50 ml). The mixture is then stirred for 40 min at room temperature.Triethylamine (10.3 ml) in isopropyl acetate (30 ml) is then added overa period of 1 h. The resulting mixture is stirred for 16 h. Citric acid(7.5 g) dissolved in water (30 ml) is added and the phases areseparated. The organic phase is washed twice with water (30 ml) andconcentrated in vacuo to give(2R,4S)-5-Biphenyl-4-yl-4-(2,2-dimethylpropionylamino)-2-methylpentanoicacid ethyl ester (3-a, R1=Piv, R2=H, R3=Et). ¹H NMR (DMSO): 1.05 (9H),1.09 (3H), 1.15 (3H), 1.54 (1H), 1.78 (1H), 2.48 (1H), 2.72 (2H), 3.97(1H), 4.00 (2H), 7.15 (1H), 7.25 (2H), 7.34 (1H), 7.45 (2H), 7.55 (2H),7.62 (2H).

Example 47 (3S,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-b,R1=H)

To a mixture of (2S,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acidethyl ester hydrochloride (3-b, R1=R2=H, R3=Et) [9:1 diastereoisomermixture [(2S,4S):(2R,4S)]] (840 mg) in isopropyl acetate (10 ml)triethylamine (418 mg) is added. The mixture is then stirred at 55° C.for 1 h and then filtered. The filtrate is heated at reflux for 24hours. To the mixture is added saturated ammonium chloride solution andthe phases are separated. The organic layer is concentrated to dryness.The residue is purified by chromatography, eluting first withIPA/Heptane 2:1 then with a mixture 1:1 to afford(3S,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-b, R1=H) and(3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-a, R1=H).Ratio of diastereoisomers determined by ¹H NMR to be 9:1[(3S,5S):(3R,5S)]. ¹H NMR (CDCl₃) for (2-b, R1=H): 1.15 (3H), 1.38 (1H),2.42 (2H), 2.63 (1H), 2.82 (1H), 3.75 (1H), 5.51 (1H), 7.17 (2H), 7.28(1H), 7.37 (2H), 7.49 (4H). Spectroscopic data for (2-a, R1=H) as inExample 6.

Example 48(3S,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one(2-b, R1=pivaloyl)

146 mg (3S,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-b,R1=H) [9:1 diastereoisomer mixture [(2S,4S):(2R,4S)]] is added to 10 mlTHF. The mixture is cooled to −78° C. and 381 μl butyllithium (1.59 M inhexane) are added. 81 μl Pivaloyl chloride is then added. After 4 h, themixture is warmed to room temperature. The mixture is then quenched bythe addition of saturated ammonium chloride solution and isopropylacetate. The phases are separated and the organic phase dried (MgSO₄)and then concentrated in vacuo. The residue is purified by columnchromatography, by eluting with isopropyl acetate/hexane 3:1 to 1:0 toafford(3S,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one(2-b, R1=pivaloyl) and(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one(2-a, R1=pivaloyl). Ratio of diastereoisomers determined by ¹H NMR to be4:1 [(3S,5S):(3R,5S)]. ¹H NMR (CDCl₃) for (2-b, R1=Piv): 1.09, 1.14(3H), 1.30 (9H), 1.34 (1H), 2.01-2.66 (3H), 3.03, 3.27 (1H), 4.31, 4.50(1H), 7.21-7.53 (9H). Diastereomeric ratio is determined by integrationof the pairs of signals at [3.03 ppm (2-a, R1=Piv) and 3.27 ppm (2-b,R1=Piv)] or those at [4.31 ppm (2-b, R1=Piv) and 4.50 ppm (2-a, R1=Piv)]from the ¹H NMR spectrum. Spectroscopic data for (2-a, R1=Piv) as inExample 5.

Example 49 1-Benzyl-5-biphenyl-4-ylmethyl-5-hydroxy-pyrrolidin-2-one

9.5 g N-Benzylsuccinimide is added to 120 ml THF and the mixture is thencooled to −78° C. A solution of 4-methylbiphenylmagnesium chloride inTHF (1.3 eq) is then added. The subsequent mixture is then stirred for 2h at −78° C. The mixture is then warmed to 10° C. and 100 ml saturatedammonium chloride solution is added. The phases are separated and theaqueous phase is extracted with toluene. The combined organic phases arewashed with water then brine and then concentrated in vacuo. The crudematerial is crystallized from toluene to give1-Benzyl-5-biphenyl-4-ylmethyl-5-hydroxy-pyrrolidin-2-one. ¹H NMR(DMSO): 1.72 (1H), 1.91 (1H), 2.27 (2H), 2.72 (1H), 2.97 (2H), 4.40(1H), 4.55 (1H), 7.21-7.66 (14H).

Example 501-Benzyl-5-[1-biphenyl-4-yl-meth-(E/Z)-ylidene]-pyrrolidin-2-one

5.5 g 1-Benzyl-5-biphenyl-4-ylmethyl-5-hydroxy-pyrrolidin-2-one is addedto dichloromethane (55 ml) at room temperature. 22 ml Trifluoroaceticacid is then added and the resulting mixture is allowed to stirovernight. The mixture is then filtered and concentrated in vacuo.Toluene (100 ml) and saturated sodium hydrogen carbonate (50 ml) areadded to the residue. The phases are separated and the organic phase isconcentrated in vacuo. The residue is added to 30 ml methanol and heatedto reflux. The mixture is then cooled to room temperature, filtered anddried in vacuo to afford1-Benzyl-5-[1-biphenyl-4yl-meth-(E/Z)-ylidene]-pyrrolidin-2-one. ¹H NMR(DMSO): (E-Isomer): 2.67 (2H), 3.07 (2H), 4.80 (2H), 5.83 (1H),7.26-7.36 (8H), 7.44 (2H), 7.59 (2H), 7.63 (2H). m/e (ES+): 340 ([MH]⁺,100%), 262 (28), 249 (63).

Example 51(R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-1,5-dihydropyrrol-2-one

1.68 g(S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1,R1=pivaloyl) is added to 10 ml toluene. The mixture is then cooled to−15° C. 5.5 ml Lithium bis(trimethylsilyl)amide (1 M in THF) is thenadded. After 1 h, a mixture of 1.3 g phenyl selenyl bromide in 10 mltoluene is added. After a further 30 min, 100 ml water is added. Thephases are separated and the organic phase concentrated in vacuo. Theresidue is taken up in 25 ml ethyl acetate and then 5.1 ml hydrogenperoxide (37%) is added at room temperature. After 1 h, the phases areseparated and the organic phase washed with a saturated sodium hydrogencarbonate solution and then dried (MgSO₄). The mixture is concentratedin vacuo and purified by column chromatography, eluting withheptane/ethyl acetate 5:1 to afford(R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-1,5-dihydropyrrol-2-one.¹H NMR (CDCl₃): 1.28 (9H), 2.70 (1H), 3.30 (1H), 4.97 (1H), 5.89 (1H),7.06 (2H), 7.19 (2H), 7.31 (2H), 7.41 (4H).

Example 52(3R,5R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methyl-2-oxo-pyrrolidine-3-carboxylicacid ethyl ester (R1=Piv; R10=OEt; R11=Me) and(3S,5R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methyl-2-oxo-pyrrolidine-3-carboxylicacid ethyl ester (R1=Piv; R10=OEt; R11=Me)

2.0 g(S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one(1-a, R1=pivaloyl) in 7.5 ml toluene is added to 26.2 ml potassiumbis(trimethylsilyl)amide (0.5 M in toluene) at −10° C. After 1 h, 568 μlethyl chloroformate is added and the mixture is stirred for 1.5 h at −5to 0° C. 733 μl Dimethylsulfate are then added and the mixture isstirred at room temperature for 1.5 h. 8 ml saturated ammonium chloridesolution are then added, along with 10 ml water and 20 ml ethyl acetate.The aqueous phase is extracted with ethyl acetate and the combinedorganic phases are then washed with brine, dried (MgSO₄) andconcentrated in vacuo. According to HNMR analysis the ratio ofdiastereoisomers is 62:38. The residue is purified by columnchromatography, eluting with ethyl acetate/heptane (1:12) to afford(3R,5R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methyl-2-oxo-pyrrolidine-3-carboxylicacid ethyl ester (R1=Piv; R10=OEt; R11=Me) and(3S,5R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methyl-2-oxo-pyrrolidine-3-carboxylicacid ethyl ester (R1=Piv; R10=OEt; R11=Me). Fractions containing bothdiastereoisomers are combined. According to HNMR analysis the ratio ofdiastereoisomers is 62:38. ¹H NMR (CDCl₃) Major diastereomer: 1.11 (3H),1.17 (9H), 1.23 (3H), 1.62 (1H), 2.26 (2H), 2.95 (1H), 4.07 (2H), 4.30(1H), 7.03-7.37 (9H). ¹H NMR (CDCl₃) Minor diastereomer: 0.99 (3H), 1.16(9H), 1.25 (3H), 1.51 (1H), 2.20 (2H), 3.13 (1H), 3.91 (2H), 4.34 (1H),7.03-7.37 (9H). Data for mixture of diastereoisomers.

Example 53(3R,5R)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1,3-dicarboxylicacid-1-tert-butyl ester-3-ethyl ester (R1=Boc; R10=OEt; R11=Me) and(3S,5R)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1,3-dicarboxylicacid-1-tert-butyl ester-3-ethyl ester (R1=Boc; R10=OEt; R11=Me)

2.0 g(S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one(1-a, R1=pivaloyl) in 7.5 ml toluene is added to 25 ml potassiumbis(trimethylsilyl)amide (0.5 M in toluene) at −10° C. After 1 h, 542 μlethyl chloroformate is added and the mixture is stirred for 1.5 h at −5to 0° C. 733 μl Dimethylsulfate are then added and the mixture stirredat room temperature for 1.5 h. 8 ml saturated ammonium chloride solutionare then added, along with 10 ml water and 20 ml ethyl acetate. Theaqueous phase is extracted with ethyl acetate and the combined organicphases are then washed with brine, dried (MgSO₄) and concentrated invacuo. According to HNMR analysis the ratio of diastereoisomers is55:45. The residue is purified by column chromatography, eluting withethyl acetate/heptane (1:6). Pure samples of each diastereoisomer areobtained for analysis. ¹H NMR (CDCl₃) Major diastereomer (R_(f) 0.13):1.28 (3H), 1.41 (2H), 1.54 (9H), 1.72 (1H), 2.43 (1H), 2.59 (1H), 3.28(1H), 4.16 (1H), 4.19 (2H), 7.22 (3H), 7.37 (2H), 7.47 (4H). ¹H NMR(CDCl₃) Minor diastereomer (R_(f) 0.17): 1.15 (3H), 1.36 (3H), 1.54(9H), 1.58 (1H), 2.36 (1H), 2.59 (1H), 3.41 (1H), 4.04 (2H), 4.31 (1H),7.16 (2H), 7.25 (1H), 7.34 (2H), 7.46 (4H).

Example 54(3R,5R)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-3-carboxylicacid (R1=H; R10=OH; R11=Me) and(3S,5R)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-3-carboxylicacid (R1=H; R10=OH; R11=Me)

252 mg(3R,5R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methyl-2-oxo-pyrrolidine-3-carboxylicacid ethyl ester (R1=Piv; R10=OEt; R11=Me) [62:38 mixture of C3-isomers]is added to 1 ml acetonitrile at 0° C. 0.3 ml 3 M Sodium hydroxidesolution is added and the mixture stirred at room temperature for 20 h.Two further 50 μl portions of 3 M sodium hydroxide are added. Stirringis continued for another 2 h. The mixture is concentrated in vacuo. 2.5ml of water is added to the residue and it is then extracted twice with1 ml toluene. 5 ml Ethyl acetate is added to the aqueous phase, which isthen cooled to 0° C. 500 μl 2 M Hydrochloric acid is added and thephases are separated. The aqueous phase is then extracted with ethylacetate. The combined organic phases are combined, dried (MgSO₄) andconcentrated in vacuo to afford(3R,5R)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-3-carboxylicacid (R1=H; R10=OH; R11=Me) and(3S,5R)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-3-carboxylicacid (R1=H; R10=OH; R11=Me). According to HNMR analysis there is a 66:34mixture of C3-stereoisomers. Identity of major isomer not determined. ¹HNMR (DMSO) [mixture of stereoisomers]: 1.21 (3H), 1.59, 1.84, 2.20, 2.29(total 2H), 2.66 (1H), 2.93 (1H), 3.81 (1H), 7.31 (3H), 7.44 (2H), 7.60(4H), 8.10, 8.15 (total 1H), 12.58 (1H).

Example 55(3R,5R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methyl-2-oxo-pyrrolidine-3-carboxylicacid (R1=Piv; R10=OH; R11=Me) and(3S,5R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methyl-2-oxo-pyrrolidine-3-carboxylicacid (R1=Piv; R10=OH; R11=Me)

44 mg (3R/S,5R)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-3-carboxylic acid(R1=H; R10=OH; R11=Me) [66:34 mixture of C3-stereoisomers] are added to10 ml toluene. 119 μl Triethylamine are added and the resulting mixturewarmed to 60° C. 52 μl Pivaloyl chloride are added and the mixture isstirred for 4 h. The mixture is then cooled to room temperature. 250 mgCitric acid in water (5 ml) is added and the phases are separated. Theorganic phase is washed with water, dried (MgSO₄) and concentrated invacuo to give(3R,5R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methyl-2-oxo-pyrrolidine-3-carboxylicacid (R1=Piv; R10=OH; R11=Me) and (3S,5R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methyl-2-oxo-pyrrolidine-3-carboxylicacid (R1=Piv; R10=OH; R11=Me). According to HNMR analysis the ratio ofC3 diastereoisomers is 65:35. Identity of major diastereomer notdetermined. ¹H NMR (CDCl₃) [Mixture of stereoisomers]: 1.19 (9H), 1.21(3H), 1.73-1.91 (1H), 2.23 (1H), 2.50 (2H), 3.12-3.33 (1H), 4.45-4.60(1H), 7.19 (1H), 7.27 (2H), 7.37 (2H), 7.46 (4H).

Example 56(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one(2-a, R1=pivaloyl) and(3S,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one(2-b, R1=pivaloyl)

63 mg (3R/S,5R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methyl-2-oxo-pyrrolidine-3-carboxylicacid (R1=Piv; R10=OH; R11=Me) [65:35. ratio of C3 isomers] is added to25 ml toluene. The resulting mixture is heated to reflux and stirred for16 h. The mixture is then cooled to room temperature and washedsuccessively with 10 ml aqueous sodium hydrogen carbonate, brine andwater. The organic phase is dried (MgSO₄) and concentrated in vacuo toafford(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one(2-a, R1=pivaloyl) and(3S,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one(2-b, R1=pivaloyl) as a 55:45 diastereomer mixture, respectively,according to the ¹H NMR spectrum.

Example 57 (3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-a,R1=H) and (3S,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-b,R1=H)

15 mg (3R/S,5R)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-3-carboxylic acid(R1=H; R10=OH; R11=Me) [66:34 mixture of C3-stereoisomers] is added to25 ml toluene. The resulting mixture is heated to reflux and stirred for16 h. The mixture is then cooled to room temperature and washedsuccessively with 10 ml aqueous sodium hydrogen carbonate, brine andwater. The organic phase is dried (MgSO₄) and concentrated in vacuo toafford (3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-a,R1=H) and (3S,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-b,R1=H) as a 29:79 diastereomer mixture, respectively, according to the ¹HNMR spectrum.

Example 581-Benzyl-5-[1-biphenyl-4-yl-meth-(E/Z)-ylidene]-1,5-dihydro-pyrrol-2-one

3.55 g N-Benzylmaleimide is added to 35 ml THF and the mixture is thencooled to 0° C. A solution of 4-methylbiphenylmagnesium chloride in THF(5.6 g, 0.69 M) is then added over 30 min. The subsequent mixture isthen stirred for 1.5 h at room temperature. Saturated ammonium chloridesolution (50 ml) is then added and the mixture stirred for 20 min. Thephases are separated and the aqueous phase is extracted with toluene.The combined organic phases are washed with water then brine and thenconcentrated in vacuo. The residue is then taken up in dichloromethane(35 ml). Trifluoroacetic acid is then added over 5 min and the mixturestirred for 3 h at room temperature. Mixture is then concentrated invacuo. Toluene (50 ml) and saturated sodium hydrogen carbonate solution(50 ml) are added and the phases are separated. The organic phase iswashed with water, then concentrated in vacuo. Methanol (2 ml) is addedto the residue and heated to reflux whereby a hot filtration isperformed. The filtrate is concentrated in vacuo to afford1-Benzyl-5-[1-biphenyl-4-yl-meth-(E/Z)-ylidene]-1,5-dihydro-pyrrol-2-one.¹H NMR (DMSO): 4.96 (2H), 6.50 (1H), 6.70 (1H), 7.26-7.76 (15H).

Example 59 1-Benzyl-5-biphenyl-4-ylmethyl-pyrrolidin-2-one

300 mg 1-Benzyl-5-[1-biphenyl-4-yl-meth-(E/Z)-ylidene]-pyrrolidin-2-oneis added to ethanol (3 ml) at room temperature. 10% Pd/C, 50% water wet(30 mg) is added and a blanket of hydrogen gas applied to the vessel.The resulting mixture is stirred for 72 h at room temperature. Thecatalyst is removed by filtration and the filtrate concentrated invacuo, to afford 1-Benzyl-5-biphenyl-4-ylmethyl-pyrrolidin-2-one. ¹H NMR(DMSO): 1.74 (1H), 1.86 (1H), 2.16 (2H), 2.63 (1H), 3.02 (1H), 3.63(1H), 4.21 (1H), 4.82 (1H), 7.23 (2H), 7.30 (3H), 7.35 (3H), 7.45 (2H),7.57 (2H), 7.64 (2H).

Example 60 1-Benzyl-5-biphenyl-4-ylmethyl-pyrrolidin-2-one

50 mg1-Benzyl-5-[1-biphenyl-4-yl-meth-(E/Z)-ylidene]-1,5-dihydro-pyrrol-2-oneis added to methanol (1.5 ml) at room temperature. 10% Pd/C, 50% waterwet (15 mg) is added and a blanket of hydrogen gas applied to thevessel. The resulting mixture is stirred for 1 h at room temperature.The catalyst is removed by filtration and the filtrate concentrated invacuo, to afford 1-Benzyl-5-biphenyl-4-ylmethyl-pyrrolidin-2-one.Spectroscopic data reported in Example 59.

Example 61(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one(2-a, R1=pivaloyl) and(3S,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one(2-a, R1=pivaloyl)

250 mg (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) is added toTHF (4 ml). The resulting mixture is then cooled to −78° C. 1.68 mlsec-butyllithium (1.3 M in cyclohexane) is then added and the resultingmixture is stirred for 0.5 h. 68 μl Methyl iodide are then added and themixture stirred for 2 h at −78° C. Saturated ammonium chloride solution(5 ml), water (3 ml) and ethyl acetate (5 ml) are added and the mixturewarmed to room temperature. The phases are separated. The organic phaseis washed with brine solution, separated, dried (MgSO₄) and concentratedin vacuo to afford(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one(2-a, R1=pivaloyl) and(3S,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one(2-a, R1=pivaloyl) as mixture (2-a) to (2-b) in a 20:80 ratio, asdetermined from ¹H NMR. Spectroscopic data for (2-a, R1=H) as in Example6. Spectroscopic data for (2-b, R1=H) as in Example 47.

The invention claimed is:
 1. A compound selected from the groupconsisting of a) a compound according to formula (2), or tautomer, orsalt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, b) a compoundaccording to formula (13), or tautomer, or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, c) a compoundaccording to formula (15), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, d) a compoundaccording to formula (16), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, e) a compoundaccording to formula (20), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, R10 is a groupwhich can be saponified and/or decarboxylated and R11 is hydrogen ormethyl f) a compound according to formula (21), or tautomer, or saltthereof,

wherein R1 is hydrogen or a nitrogen protecting group, and g) a compoundaccording to formula (22), or tautomer, or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group.
 2. A compoundaccording to claim 1, wherein the compound of formula (2) has aconfiguration according to formula (2-a), or tautomer, or salt thereof,

the compound of formula (13) has a configuration according to formula(13-a), or tautomer thereof,

the compound of formula (16) has a configuration according to formula(16-a)

and the compound of formula (20) has a configuration according toformula (20-a)


3. A compound according to claim 1 wherein the compound according toformula (2), or tautomer, or salt thereof, is in crystalline form.
 4. Acompound according to claim 2 wherein the compound according to formula(2-a), or tautomer, or salt thereof, is in crystalline form.
 5. Acompound according to claim 1, wherein in the compound of formula (2-a)R1 is hydrogen or a nitrogen protecting group selected from pivaloyl andt-butyloxycarbonyl (BOC).
 6. A process for producing a compoundaccording to formula (3) or a salt thereof

comprising reacting a compound according to formula (2), or tautomer, orsalt thereof,

with a ring opening agent, wherein in the above formulae R1 and R2 areindependently, of each other, hydrogen or a nitrogen protecting groupand R3 is hydrogen or alkyl.
 7. A process according to claim 6characterized in that a compound having a configuration according toformula (3-a) or a salt thereof is obtained

wherein R1 and R2 are independently, of each other, hydrogen or anitrogen protecting group and R3 is hydrogen or alkyl.
 8. A processaccording to claim 6, wherein the compound of formula (2) is prepared bya process comprising methylating a compound according to formula (1), ortautomer, or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group.
 9. A processaccording to claim 8, wherein the compound of formula (1) has aconfiguration of formula (1-a), or tautomer, or salt thereof,

and the compound of formula (2) has a configuration according to formula(2-a)


10. A process according to claim 8, wherein the methylating processcomprises a) treating the compound of formula (1), or tautomer thereof,or salt thereof, with a base and a methylating reagent, or b) a processcomprising i) treating the compound of formula (1), or tautomer thereof,or salt thereof, first with a base and then with a compound of theformula YCO₂R, wherein Y is halogen or —OR′ and wherein R and R′ areindependently selected from alkyl, aryl and arylalkyl, to obtain acompound of formula (20), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group, R11 is hydrogenand R10 is OR wherein R is alkyl, aryl or arylalkyl; ii) reacting theresulting compound of formula (20) with a base and a methylating reagentto obtain a compound of formula (20), or salt thereof, wherein R1 ishydrogen or a nitrogen protecting group, R11 is methyl and R10 is ORwherein R is alkyl, aryl or arylalkyl; iii) optionally, treating thecompound of formula (20) wherein R1 is hydrogen or a nitrogen protectinggroup, R11 is methyl and R10 is OR wherein R is alkyl, aryl orarylalkyl, with a saponification reagent, to obtain a compound offormula (20), or salt thereof, wherein R1 is hydrogen or a nitrogenprotecting group, R11 is methyl and R10 is OH; and iv) treating thecompound obtained in step (b) or (c) under decarboxylation conditions toobtain the compound of formula (2).
 11. A process according to claim 10,wherein the compound of formula (20) has a configuration of formula(20-a)


12. A process according to claim 8, wherein the compound of formula (1)has a configuration of formula (1-a), or tautomer, or salt thereof,

and wherein the compound according to formula (2) is produced in a ratioof diasteromers (2-a) to (2-b)

of at least 60:40.
 13. A process according to claim 6, wherein R1 and R2are hydrogen and R3 is an ethyl group.
 14. A process according to claim6, wherein the obtained compound of formula (3)

wherein R1 and R2 are independently, of each other, hydrogen or anitrogen protecting group and R3 is hydrogen or alkyl, is furtherreacted to produce a compound according to formula (18) or a saltthereof


15. A process according to claim 14, wherein the compound of formula (3)has a configuration of formula (3-a)